Summary Basis of Decision for Velcade

3.3.1 Human Pharmacology

Pharmacodynamics

The inhibitory effects of bortezomib on proteasome were evaluated in three Phase 1 dose-escalation studies and two Phase 2 studies. The Phase 1 dose-escalation studies were conducted to define toxicity profiles and determine the appropriate dosage and schedule for Phase 2 development. The Phase 1 trials included 123 patients with advanced cancers, and IV bolus unit doses of bortezomib ranging from 0.13 mg/m² to 2.0 mg/m². The anti-tumour activity noted in these Phase 1 studies led to the initiation of two Phase 2 studies (M34100-025 and M34100-024) on patients with multiple myeloma³.

Proteasome inhibition across the Phase 1 and 2 studies showed similar mean maximum inhibition and inter-individual variability. The control 20S proteasome values before treatment were variable, therefore explaining the high variability of data obtained with low doses of bortezomib and those recorded before subsequent doses of bortezomib. According to the sponsor, the assay was robust for high levels of proteasome inhibition observed with clinically relevant doses of bortezomib; there was concurrence of dose-response relationships for maximum inhibition obtained across studies with consistency of results at different timepoints within treatment cycle and across different cycles and a close range of values of maximal inhibition across the studies. Nevertheless, a large variability of the levels of inhibition and its kinetic of recovery was observed.

Dose-response and a plasma concentration response relationship with proteasome inhibition exist, but are based on a limited number of patients with pharmacokinetic/ pharmacodynamic data. The time course of proteasome inhibition was characterized by partial recovery of proteasome activity inhibition within 6-24 hours followed by persistent variable low levels of inhibition up to the next scheduled dosing. The dose range where a high level of inhibition was observed was between 1.0 mg/m² and 2.0 mg/m². In patients with refractory multiple myeloma, the level of proteasome inhibition seemed to be unrelated to the observed response rate. Multiple analyses revealed no significant relationship between degree of 20S proteasome activity and response to treatment or maximum change from baseline in M-protein.

The regimen selected for the Phase 2 studies was based on preclinical pharmacodynamic data and results of the Phase 1 studies. The studies demonstrated a lack of correlation between proteasome inhibition and toxicity. Evaluation of dose-limiting toxicities was based on clinical observation, for dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). The MTD of bortezomib ranged from 1.04 mg/m² to 1.6 mg/m² depending on the dosing schedule. Intermittent administration resulted in high but transient inhibition of proteasome activity and was better tolerated than sustained inhibition, with return towards the pre-treatment level and recovery of proteasome activity between doses and cycle, minimizing toxicity. The twice-weekly dosing regimen was based on return to baseline (approximating 72 hours) and the supporting data that the earlier rest period after 2 weeks of twice-weekly dosing was better tolerated. However, return to baseline of proteasome activity was not a prerequisite for continuing treatment.

No formal studies to assess the effects of age, gender, race, impaired renal or hepatic function and concomitant medications on the pharmacokinetics and duration of 20S proteasome inhibition of bortezomib have been reported.

Early disposition kinetics of bortezomib in a subset of patients with reduced creatinine clearance indicate that disposition is not affected by variation in creatinine clearance (from 31 mL/min to 169 mL/min, which is normal renal function to moderate impairment) but no patients had severe renal impairment (creatinine clearance of <30 mL/min). The potential effect of moderate to severe renal impairment on inhibition of 20S proteasome activity by bortezomib and terminal elimination were not evaluated in this study. Phase 2 multiple myeloma enrolled 10 patients with a creatinine clearance between 10 mL/min and ≤30 mL/min but the levels were not measured at peak and not studied over many cycles.

³ Several distinct mechanisms have been proposed in the anti-neoplastic effects of bortezomib in multiple myeloma: inhibition of cell growth signalling pathways and induction of apoptosis; inhibition of nuclear factor-κβ activation with inhibition of cellular adhesion molecules, angiogenic factors and IL-6 production as well as reduction of adherence of myeloma cells to bone marrow stromal cells. Multiple myeloma cells over-express IL-6 which have been shown to have a major growth and anti-apoptotic effect in multiple myeloma cells.

Pharmacokinetics

Only limited data is available for the pharmacokinetic characterization of bortezomib at the recommended dose in multiple myeloma patients. However, the submitted data is considered sufficient to assess the benefit/risk assessment for Velcade in the treatment of relapsed and refractory multiple myeloma.

Results from the plasma concentration-time profiles of bortezomib showed rapid and extensive distribution from the systemic circulation; the initial distribution phase had an estimated half-life of 30 minutes followed by an elimination half-life between 9 and 15 hours. Following multiple doses of bortezomib, systemic exposure (AUC) doubled and this was associated with decreased clearance. The terminal elimination half-life increased approximately two fold. Similar results were seen in the animal studies.

The kinetic profile of bortezomib was not extensively characterized. The sponsor would be required to submit additional studies to support a submission for expanded use.

The submitted data is insufficient for the following reasons:

• Data was limited with very few patients as monotherapy. Sampling was also limited in these patients coupled with samples below the limit of quantification for the assay.
• Kinetics were evaluated at a narrow dose range with few conclusions drawn on dose proportionality.
• High interindividual variability was reported with no clear kinetic reason identified (rapid distribution with infrequent sampling times has been proposed but not confirmed).
• Accumulation was observed after 3 doses in cycle 1 in patients treated with borterzomib and gemcitabine in combination, with no data as a single agent or multiple cycles. Data was limited but consistently showed accumulation of borterzomib in humans. The decrease in clearance after repeated doses could possibly result in accumulation and toxicity over time if no treatment adjustments are made.
• Elimination routes were not studied in humans. Animal studies provided data for hepatic, urinary and biliary excretion routes, suggesting both hepatic and renal clearance as being quantitativily important. There is insufficient clinical data available for analysis of liver impairment or moderate to severe renal impairment on the terminal disposition kinetics of borterzomib.
• No interaction studies (CYP 3A4 and CYP 2C19 inducers and inhibitors) were conducted.
• The effects of gender, age or race on the pharmacokinetics have not been investigated.
• Transfer of borterzomib across the placenta and secretions in bile have not been determined.

3.3.2 Clinical Efficacy

Two Phase 2 multicentre, open-label, non-comparative studies (M34100-025 and M34100-024) used bortezomib alone or in combination with dexamethasone to establish the efficacy and the safety of bortezomib in relapsed (and refractory, in Study M34100-025) multiple myeloma, for a maximum duration of 8 cycles.

The pivotal Study M34100-025 enrolled 202 patients, 91% of which had relapsed and refractory multiple myeloma, with at least two prior lines of therapy at a dose and schedule of 1.3 mg/m² administered IV twice weekly for two weeks, followed by a 10 day rest period, for a maximum of 8 cycles of treatment. Supporting efficacy and safety data was provided from Study M34100-024 which randomized 54 patients relapsed after front-line therapy to one of two doses of bortezomib, 1.0 mg/m² or 1.3 mg/m² administered on the same schedule as in Study M34100-025. Dexamethasone was allowed in both studies for patients not responding to bortezomib alone. The primary objective in these Phase 2 studies was overall response rate to treatment with bortezomib alone using response as a surrogate for survival, with secondary endpoints being time to progression (TTP) and survival.

Efficacy measurements included serial electrophoretic analysis of the serum proteins to determine the amounts of immunoglobulins in the serum⁴. Other measurements included urine electrophoresis and immunologic typing of the M-component, and analysis of the bone marrow biopsy and aspirate, laboratory data and skeletal survey. The primary objective was to determine overall response rate. The secondary objectives and efficacy analyses included time to event parameters, time to response, duration of response, time to progression, survival, clinical benefit parameters (improvement in non M-protein immunoglobulins, renal function, haemoglobin, performance status, quality of life, reduction of myeloma paraprotein levels). The efficacy assessment and determination of disease response was based on criteria developed by Blade criteria⁵, with all data of response to treatment reviewed by the Independent Review Committee (IRC).

Five patients of 193 patients from the ITT population (patients treated with any amount of study drug) were excluded from the efficacy analyses because of inadequate prior therapy. Of the 188 evaluable patients, complete responses⁶ (CR) occurred in 5 (2.7%) and partial responses⁷ (PR) in 47 (25%) of the patients. Response was rapid at 38 days, and consistent across different response categories.

Supporting data was found in Study M34100-024; the paraprotein response to all-treatment showed 50% of the patients at 1.3 mg/m² (41% in 1.0 mg/m²) had ≥50% reduction of M-protein levels. These results provided evidence for activity at the 1.0 mg/m² dose level and supports continued use of bortezomib at this dose for patients reduced from a higher dose secondary to adverse events. In Study M34100-025, results also showed that response rates to bortezomib were independent of dose reductions⁸. From the group of subjects that were administered bortezomib alone, 32 (42%) of the 76 patients with dose reductions for adverse events had a response to treatment.

⁴ Serum of patients with plasma cell tumours have an increased gamma globulin region with a sharp spike of the M (monoclonal) component. The amount of M-component in the serum is a reliable measure of tumour burden.

⁵ The Blade criteria are available from the following website: http://www.multiplemyeloma.org/treatments/3.08.02.table_1.html.

⁶ Complete response required 100% disappearance of the original monoclonal protein from blood and urine on at least 2 determinations at least 6 weeks apart by immunofixation and <5% plasma cells in the bone marrow on at least two determinations for a minimum of six weeks, stable bone disease and calcium.

⁷ Partial response required ≥50% reduction in serum myeloma protein and ≥90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks, stable bone disease and calcium.

⁸ During Phase 2 studies, protocol specified dose modifications for Grade 3 or 4 drug-related toxicities to re-start at a reduced dose of 1.0 mg/m² upon resolution to Grade 1 or better. Further reduction from 1.0 mg/m² to 0.7 mg/m² were also permitted.

Subpopulations

In the Phase 2 studies, there was some evidence that response rates to bortezomib were likely to predict clinical benefit, with biological activity being shown by both objective data (reductions in measurable disease parameters including abnormal levels of serum paraprotein and % bone marrow plasma cells) as well as subjective data.

The final demonstration of efficacy relied on the anti-tumour activity results and response rates from Study M34100-025, with supportive data from M34100-024. Using each patient as their own control, there was a 2- to 4- fold increase in TTP on bortezomib alone compared to previous therapy, with a median survival of 16 months which is better than expected in this population.

Study M34100-024 was a low-powered study that assessed a different population (not refractory) than the one studied in the pivotal study, and assessed two doses (1.0 mg/m² and 1.3 mg/m²) of bortezomib. Both the mean and median total dose, and duration of treatment were higher in the 1.0 mg/m²group. Nevertheless, the statistical summaries show differences consistent with dose response with bortezomib monotherapy (response rate and reduction of paraprotein in both dose groups). Although the small sample size precludes any definitive statements, there is some evidence for a dose effect with respect to both efficacy and safety. Therefore, the higher dose (1.3 mg/m²) was recommended as the optimal starting dose with a dose reduction to 1.0 mg/m² for toxicities.

Additional clinical benefit analyses were performed in responding patients with relapsed and refractory multiple myeloma. These analyses were exploratory in nature; they were not prospectively defined in the protocol, and evaluating clinical benefit from the uncontrolled and open setting they were drawn from does not give valuable information. Nevertheless, responding patients (CR, PR) provided evidence of additional clinical benefit including improvement in haemoglobin with decline in transfusion support and improvement in levels of non-myeloma immunoglobulins. Clinical benefit analyses may be confounded by concomitant treatment and procedures, as there were no restrictions on use of erythropoietin or transfusion support during the study. The data was analyzed for clinical benefit in the treatment phase only, data on the duration of these responses in the follow-up period was not collected.

Tumour response cannot be seen as a surrogate marker for clinical benefit but there is support from the literature that a correlation exists between response and survival in relapsed multiple myeloma, and that Blade criteria are a surrogate reasonably likely to predict clinical benefit. The data support the proposal that durable complete remissions, as well as patients with partial response, in response to bortezomib, results in some clinical benefit both in terms of survival and in improvement of other complications of myeloma.

No adequate and well controlled trials have been presented and clinical benefit endpoints cannot be reliably measured without reference to a concurrently studied active comparator agent. Confounding factors in evaluation of safety and efficacy across dose groups included heterogeneity of patients based on types and number of front-line therapy administered, and dose group differences in baseline factors. Results of comparative trials are required to assess the association between response and duration of survival and the true clinical benefit of bortezomib in patients with relapsed and refractory multiple myeloma.

3.3.3 Clinical Safety

Three Phase 1 studies enrolled a total of 123 patients with advanced haematological and solid tumours. The patients were administered bortezomib in unit doses ranging from 0.13 mg/m² to 2.0 mg/m² in three different dosing regimens.

Data from the Phase 1 studies showed that 54% of the patients discontinued; 37% due to progressive disease which was lower in the >1.3 mg/m² group then in the <0.7 mg/m² group, and 21% due to adverse events or toxicity. A dose-relationship was seen with the incidence of adverse events leading to discontinuation; 7% at <0.7 mg/m², 16% at 0.7 mg/m²-1.3 mg/m² and 37% at >1.3 mg/m² with the most common being fatigue (3%) and dyspnea (2%). Dose limiting toxicities (DLT) consisted of diarrhea and peripheral sensory neuropathy at 1.56 mg/m² when administered at the same regimen as in the Phase 2 trials. Thrombocytopenia, nausea, constipation, diarrhea, vomiting, and headache all increased with dose. In 37% of the patients at least one serious adverse event was reported, mostly pyrexia at 5%, dyspnea and diarrhea at 4%, abdominal pain and hypotension non-organ specific (NOS) at 2%. The incidence of serious adverse events increased with dose. Serious adverse events consisted of respiratory failure, pneumonia, dehydration, portal vein thrombosis, sepsis and dehydration, increased bilirubin, infection and ileus with peripheral neuropathy, ascites, cases of pulmonary embolism, pericardial effusion, cardiac arrest and hypotension, abdominal pain and bowel obstruction, impaction, pleural effusion, peripheral neuropathy, acute renal failure, sepsis and deep venous thrombosis. There was a case of possible neurogenic postural hypotension for a patient with severe syncope and orthostatic hypotension. Another patient had severe generalized sensorimotor axonal polyneuropathy, small bowel obstruction and a case of severe respiratory distress that caused death after the study.

Two Phase 2 studies (M34100-024 and M34100-025) enrolled 256 patients with multiple myeloma, 28 were in the 1.0 mg/m² dose group and 228 in the 1.3 mg/m² dose group. All were assessed for safety.

The data from the Phase 2 studies showed consistency with the Phase 1 studies with regards to the target organs of toxicity, as well as, dose relationships with adverse events. The lower dose, 1.0 mg/m², was more tolerable than the 1.3 mg/m² dose; 39% of the patients at 1.3 mg/m² completed the study compared to 67% in the 1.0 mg/m² dose group, and 23% of the patients at 1.3 mg/m² discontinued secondary to adverse events compared to 11% of the patients at 1.0 mg/m². Increased exposure to bortezomib was associated with increased incidence rates of several of the most common reported events (constipation, pyrexia, dyspnea, dizziness, depression, anxiety, rigors, hypoesthesia and pain), with increased serious adverse events and discontinuations. The following adverse events were reported more frequently (≥10%) in the 1.3 mg/m² dose group (N=228) than in the 1.0 mg/m² group (N=28): nausea (64% vs 46%), diarrhea (51% vs 25%), constipation (43% vs 32%), thrombocytopenia (42% vs 32%), vomiting (36% versus 14%), anorexia (32% vs 11%), peripheral neuropathy NOS (30% vs 18%), neutropenia (23% vs 11%), and dehydration (18% versus 0%).

In Study M34100-025, where most patients were treated with the proposed dosage of 1.3 mg/m² in the first cycles, the most common causes of discontinuation were: peripheral neuropathy (4%); thrombocytopenia (4%); diarrhea and disease progression (3%); and dehydration and syncope (2%). Results showed that 68% of patients had at least one Grade 3 adverse event with the most common being thrombocytopenia (28%); fatigue (12%); peripheral neuropathy (12%); and neutropenia (11%). The most common Grade 3 gastrointestinal adverse events were vomiting (8%), diarrhea (7%), and nausea (6%).⁹ At least one dose was held back in 64% of the patients because of an adverse event (thrombocytopenia 17%, neutropenia/decreased neutrophil count 14%, peripheral neuropathy 10%, and nausea 8%).

Grade 4 events occurred in 14% of the patients treated with 1.3 mg/m² and serious adverse events in 50% (39% with 1.0 mg/m²). The most common Grade 4 events with the 1.3 mg/m² dose were thrombocytopenia (3%) and neutropenia (3%). The most common serious events were pyrexia (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), dehydration (5%) and nausea (4%), with adverse events leading to discontinuation in 18% of the patients (11% at 1.0 mg/m²). The most commonly reported adverse events leading to discontinuation were peripheral neuropathy (5%), thrombocytopenia (4%), diarrhea (2%) and fatigue (2%). It is important to note that 40-50% of all doses at 1.3 mg/m² were held or reduced. Of the 98% that received a starting dose of 1.3 mg/m², only 28% received this dose throughout the study, while 33% had dose reductions.

In both Phase 2 studies, 11 patients (5%) died within 20 days after the last bortezomib dose (or any time after if considered to be related to bortezomib). Most died of disease progression but two patients died of drug-related incidences; one of cardiopulmonary arrest 9 days after the last dose and the other of respiratory failure secondary to diaphragmatic failure due to myopathy 39 days after the last dose. There were no clinically relevant differences in Grade 3 or 4 events, serious adverse events, or discontinuations noted by age, gender, race, and body surface area. The incidence rates of Grade 3 or 4 events, serious adverse events or discontinuation due to adverse events was not higher among patients with higher levels of proteasome activity inhibition.

⁹ The criteria (CTCAE) for the grading of adverse events for oncology clinical trials are available from the National Cancer Institute website: http://ctep.cancer.gov/reporting/ctc.html.

Adverse Events

Note: The following results were taken from the two Phase 2 studies (M34100-024 and M34100-025) unless specified otherwise. The adverse events were separated by dosage (1.0 mg/m² and 1.3 mg/m²) with the majority in the 1.3 mg/m² dose group.

Gastrointestinal Events: Results showed 88% of the patients had at least one treatment-emergent adverse event (nausea, diarrhea, constipation, vomiting), 21% had Grade 3 or 4 events, and 13% of the patients (all were in the 1.3 mg/m² dose group) had serious adverse events. The most common event was nausea (64%), diarrhea (51%), constipation (43%), vomiting (36%), dyspepsia (13%) and abdominal pain NOS (13%). The mechanism is unknown. These events had an early onset and continued for several cycles before resolution, with a trend towards increased incidence with dose. Cases of ileus were also noted.

Metabolism and Nutrition Disorders: Results showed 63% of the patients had a treatment-emergent adverse event in this category and 18% had Grade 3 or 4 events. The most common event was anorexia and decreased appetite NOS (43%), dehydration (18%, Grade 3 in 7%, serious in 5%), and cases of Grade 4 hypercalcemia and hyperuricemia.

Cardiac Disorders: The incidence of cardiac disorders was 20%; 4% of the patients had serious adverse events, 5% of the patients had Grade 3 or 4 events, including severe cardiac heart failure (acute development or exacerbation), pulmonary edema, amyloidosis, cardiac arrest and cardiorespiratory arrest, ventricular extrasystoles, pulmonary embolism, atrial fibrillation, peripheral embolism, bipedal edema, severe sinus and ventricular tachycardia, and ventricular arrhythmias.

Hypotension (orthostatic and postural): Results showed 12% of the patients had hypotension (NOS, orthostatic and postural) of which half had pre-existing hypertension. Grade 3 events occurred in 4% of the patients. The mechanism for hypotension is currently unknown but it could be associated with autonomic neuropathy. One third of the patients with hypotension also had concurrent peripheral neuropathy. Ten patients (4%) had a concurrent syncopal episode with their hypotension.

Syncope: Severe syncope was reported for 17 patients in the 1.3 mg/m² dose group, 13 patients had Grade 3 events, 4 patients discontinued because of syncope, and 3 patients needed dose modifications, many without underlying cardiovascular reserve problems or dehydration.

Autonomic Neuropathy: One patient was diagnosed with autonomic neuropathy and another with dysautonomia. An association of peripheral neuropathy with syncope or dizziness was noted. Peripheral neuropathy was reported as a serious event in 6 patients, including 4 who had to be hospitalized for the event, of which 3 had concurrent syncope or dizziness. In view of this association and the incidence of hypotension, syncope, and gastrointestinal adverse effects with the mechanism of action being unknown; drug induced autonomic neuropathy is strongly suspected. Special precautions should be taken in patients with increased risk of hypotension (dehydration, antihypertensive medication, history of syncope). A cautionary statement on this issue has been incorporated in the Product Monograph, and the sponsor has planned a study to assess the possibility of autonomic neuropathy.

Nervous System Disorders: Results showed 73% of the patients had at least one treatment-emergent nervous system disorder; 25% had Grade 3 or 4 events (2 patients with Grade 4). The nervous system disorders included peripheral neuropathy NOS (30%), headache NOS (28%, 4% Grade 3), dizziness (21%), paresthesia (12%), hypoesthesia (11%), mental status changes and confusion, emotional disturbance, irritability, restlessness and mood swings, anxiety, insomnia, dizziness and syncope, and rarely abnormal gait, haemorrhagic stoke, and cranial palsy. Most cases of peripheral neuropathy were sensory but cases of sensorimotor were noted. A low incidence of seizures was also reported.

Peripheral Sensory Neuropathy: In the Phase 1 study, peripheral sensory neuropathy was a dose-limiting toxicity. There was a linear increase in estimated probability as a function of cumulative dose. In the 1.3 mg/m² dose group, 34% of the patients reported symptoms of neuropathy as "quite a bit" or "very much", and 18% had difficulty walking. In a neurological exam, 85% of the patients at 1.3 mg/m² reported sensory or motor symptoms and 51% of the patients had functional impairment associated with the symptoms reported. The overall incidence of peripheral neuropathy as a serious adverse event was more prominent in patients with a baseline condition; the incidence of Grade 3 events was much lower if there was no peripheral neuropathy at baseline. Reversibility was only demonstrated in 14% of the patients who had more severe symptoms. Reversal of toxicity in most target organs was observed following recovery with exception of axonal degeneration of the sciatic nerve. It is unknown if the potential for similar results exist in other nerves and this safety concern has been incorporated in the Product Monograph. The mechanism of Velcade-induced peripheral neuropathy is unknown and the complete time course of this toxicity is not fully characterized. Careful risk/benefit assessment is necessary if there is pre-existing severe neuropathy.

Asthenic Conditions: Results showed that 65% of the patients had at least one asthenic condition; 18% had Grade 3 or 4 events, 52% had fatigue.

Blood and Lymphatic System Disorders: Results showed no evidence of cumulative bone marrow toxicity; myelosuppression was uncommon. The most common haematological toxicity was thrombocytopenia. Results showed that it was dose-related. Thrombocytopenia occurred early during the dosing period (days 1-11) and the platelet count returned to baseline during the rest period of the treatment cycle (days 12-21). Thrombocytopenia occurred in 65% of the patients at the 1.3 mg/m² dose (46% at 1.0 mg/m²); 27% of the patients at the 1.3 mg/m² dose had Grade 3 events (32% at 1.0 mg/m²), 3% had Grade 4 events, and 2% were classed as serious. Serious haemorrhagic complications were reported, both gastrointestinal and intracerebral. The possibility of these conditions has been clearly identified in the Product Monograph. Patients with risk factors for bleeding should be monitored carefully and prophylactic treatment should be considered in view of potential important clinical sequelae. Other common blood disorders were anemia (30% of the patients, Grade 3 in 9%) and neutropenia (23% of the patients, Grade 3 in 13%).

Infections: Results showed 61% of the patients had at least one treatment-emergent adverse event in this category; 13% had a Grade 3 or 4 event.

Pyrexia (>38): Results showed 36% of the patients had elevated body temperatures; 4% had Grade 3 or 4 events, 7% were classed as serious, 13% were from a clinically significant infection. Autonomic dysfunction cannot be excluded as one of the underlying mechanisms.

Musculoskeletal Disorders: Results showed 64% of the patients had at least one treatment-emergent adverse event in musculoskeletal and connective tissue disorders; 21% were Grade 3, 5% serious, 3% led to discontinuation. Common adverse events were arthralgia, pain in limb, bone pain, back pain, muscle cramps, and myalgia.

Electrolyte Imbalance: The mechanism for electrolyte imbalance is unknown. In the Phase 1 study, hyponatremia was a dose-limiting toxicity. Hyponatremia was in 8% of the patients; 5% had Grade 3. Hypokalemia was in 7% of the patients; 2% had Grade 3. Hyperkalemia was reported in 4% of the patients. Hypomagnesemia and hypophosphatemia were also reported.

Respiratory/Thoracic Disorders: Results showed 57% of the patients had at least one treatment-emergent adverse event in this category. The most common was dyspnea in 22% of the patients; 7% had Grade 3 or 4 events, 8 patients had severe or life-threatening, and 2 patients had respiratory failure. The incidence of dyspnea NOS increased with the age categories and differed by >10%. Coughing was also reported frequently (17%) and rare cases of hemoptysis and pleural effusion were observed.

Renal and Urinary Disorders: Results showed 23% of the patients had one treatment-emergent adverse event; 5% had a Grade 3 or 4 event, and 4% had renal failure NOS. Creatinine abnormalities with treatment were noted in 29% of the patients; Grade 3 in 3%, severe or life-threatening renal failure in 4 patients.

Immuno Complex-Mediated Reactions: One patient with multiple myeloma in the Phase 1 study at a dose of 1.04 mg/m² had a immuno complex-mediated hypersensitivity reaction, a serum sickness reaction with rash and dyspnea as a serious adverse event. In the Phase 2 study, one patient had diffuse polyarthritis and rash, and one case of acute renal failure.

Tumour Lysis Syndrome: The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Special Populations

Renal Impairment: The studies excluded patients with severe renal impairement, and the 6 patients that had creatinine clearances of ≤30mL/min in the 1.3 mg/m² dose group experienced severe adverse events. Patients with mild to moderate renal impairment had similar rates of adverse events, but the incidence of serious adverse events increased with decreased renal function. The most common events were neutropenia, and renal and urinary disorders.

Hepatic Impairment: Conclusions on the safety profile of bortezomib in patients with liver impairment are not available as patients with abnormal liver function were excluded from the Phase 2 studies. Bortezomib is metabolized by the liver, therefore the clearance may be decreased in patients with liver function abnormalities. These patients should be treated with extreme caution and be monitored for toxicity. A cautionary statement on this issue has been incorporated in the Product Monograph.

Reproduction: Fertility studies were not performed. Animal toxicity studies with rats showed degenerative effects in the ovary and testes.

Pregnant Women and Nursing Mothers: Studies did not include pregnant or lactating women.

Pediatrics and Adolescents: The safety and effectiveness of bortezomib in children and adolescents have not been established.

Diabetic Patients: Diabetic patients on oral hypoglycemic agents experienced hypoglycemia and hyperglycemia on bortezomib. Close monitoring of glucose levels is therefore recommended.

Elderly Patients: Patients who were >65 years of age (35% of the patients) experienced a lower response rate and higher incidence of Grade 3-4 adverse events (74% ≤50 to 85% >65), mostly anorexia, dehydration, hypotension, cardiac disorders (congestive heart failure) and respiratory disorders (dyspnea).

Drug-Drug Interactions: Concomitant use with medications that are inhibitors or substrates of 2D6 and 3A4 isozymes were recorded, although no formal drug interactions studies were conducted. The inhibitors included amiodorane, cimetidine, and ritonavir and the substrates were amiodarone, codeine, dexamethasone, odansetron, haloperidol, lidocaine and propanolol. The incidence of Grade 3 or 4 adverse events was greater for patients receiving substrates (89% versus 78%) and patients receiving inhibitors of these isoenzymes had higher Grade 3, 4 or serious adverse events (89% versus 73% and 60% versus 45% for serious). Nausea, vomiting, anorexia, constipation, weakness, thrombocytopenia and neutropenia seem higher in patients receiving substrates and anorexia, insomnia and dyspepsia were more common if inhibitors of 2D6 3A4 were co-administered.

Conclusion

The safety experience in patients with multiple myeloma is limited and additional toxicities are likely to be observed upon wider use of this agent. Limitations of the safety database are based upon exclusion criteria in the trials: hepatic dysfunction, severe renal dysfunction, severely debilitated patients, recent myocardial infarction, hypercalcemia, pregnancy, lactation and pediatric age group. There were no formal pharmacokinetic or pharmacodynamic studies in these sub-groups of patients. The Warning and Precautions section of the Product Monograph provides guidance on the use of Velcade* in these special populations with the exception of those experiencing debilitation, myocardial infarction, and hypercalcemia. Additional precautions may be needed in these populations, as determined by the administering physician.

3.3.4 Issues Outstanding

Under the NOC/c policy, the following clinical commitments were required of the sponsor:

• Provide complete study reports of Study M34101-039, "An International, Multi-Center, Randomized, Open-label Study of Velcade* Versus High-Dose Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma.
• Include monitoring and follow-up of adverse events from Study M34101-039 as well as events noted in post-marketing data (cardiovascular, seizures) and major safety concerns identified (neurological, psychiatric, immunological).