Summary Basis of Decision for Revlimid ®

3.3.1 Pharmacodynamics

In healthy volunteers, multiple dosing with lenalidomide appeared to have an effect upon the immune response. The highest dose used in the multiple dose pharmacodynamic (PD) study was 200 mg/day. Dosing occurred once in the mornings of Days 1 and 8 and twice daily on Days 2 to 7 inclusive. A statistically significant dose-related decrease in both CD4 and CD8 blood counts was observed from Day 4 onwards. For CD4 counts, the magnitude of the decreases was relatively constant (approximately 300/mm³) on Days 4, 6, and 8, with values approaching baseline levels by the post-study assessment. By contrast, decreases in mean CD8 counts were most pronounced on Day 8 (242/mm³), with levels still considerably lower than the baseline value at the post-study assessment. However, the affects of lenalidomide on CD4 and CD8 blood counts in MDS patients remains unknown.

PD effects of lenalidomide in eight healthy subjects included a gradual increase in alanine transaminases (ALT) levels relative to baseline between Days 4 and 9 in three individuals following administration of lenalidomide, with the highest values observed on Day 9. A fourth subject demonstrated a sharp increase in aspartate aminotrasferase (AST), ALT, and creatinine kinase (CK), in association with a number of adverse events, on Day 10. The pattern of the biochemical changes observed was characteristic of that seen with skeletal muscle damage. Both platelets and lymphocyte counts were found to decrease from Day 4 onwards.

Additional studies are required to assess the effects of lenalidomide on adult and fetal hemoglobin. The non-clinical and clinical data are conflicting, therefore the proof of concept has not been clearly established for the proposed indication. Data regarding the effect of Revlimid^® on adult and fetal hemoglobin levels using hemoglobin electrophoresis will be provided with the PK/PD ongoing commitment Study CC-5013-PK_002.

3.3.2 Pharmacokinetics

Absorption

Following oral administration, lenalidomide was rapidly absorbed in healthy volunteers; the maximum concentration was obtained within 1.5 hours. Preliminary PK data was requested from an ongoing PK/PD study conducted with patients with Low-or-Intermediate-1-risk MDS. In patients with MDS, drug exposure was almost twice as high as that obtained in healthy subjects who received the same dose of 10 mg of lenalidomide. Bioavailability studies of lenalidomide in humans were not available. A future study will be performed to assess the bioavailability of lenalidomide in male and female patients.

Distribution

Plasma protein binding of radiolabelled lenalidomide was approximately 23-29% in vitro.

Metabolism

The metabolic profile and circulation of lenalidomide metabolites in human biomaterials (plasma, urine, or feces) were not studied.

Lenalidomide showed no inhibition or induction of cytochrome P450 enzymes in vitro.

Excretion

Lenalidomide excretion was renal, with 67% of unchanged drug recovered in the urine. Half-life of elimination was approximately 3 hours. The drug clearance was 33% slower in MDS patients compared to healthy subjects. There was a lack of data for patients with renal impairment. The recommendation for lower starting doses in patients with renal insufficiency is included in the Product Monograph.

Drug Interactions

In vivo, a dose of 10 mg lenalidomide increased the digoxin plasma concentration and exposure (AUC) by 14%. Both warfarin and digoxin had no measurable effects on Revlimid^® pharmacokinetics in healthy volunteers. Therefore, monitoring of Revlimid^® levels was deemed unnecessary when co-administered with these drugs.

3.3.3 Clinical Efficacy

Two Phase II studies were submitted to support the clinical efficacy and safety of Revlimid^® for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion (del) 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Study MDS-001 was a small (n = 45), pilot, dose-finding study that was conducted to gain preliminary information on the efficacy and safety of lenalidomide in subjects with MDS, to identify the subpopulations of subjects with MDS who respond to lenalidomide, and to identify a safe and effective dose for use in subsequent confirmatory studies. The erythroid response rate was 44% (19/43) in subjects who had Low- or Intermediate-1-risk MDS. The major finding of this study was that patients with a del 5 (q31-33) cytogenetic abnormality appeared to be particularly responsive to Revlimid^®. The erythroid response rate in this targeted population of patients was 69% (9/13), and this was associated with a median increase of 5.3 g/dL in hemoglobin and with major cytogenetic responses in 85% (11/13) of the patients. Overall, the results of this study suggested that lenalidomide, administered at an initial dose of 10 mg/day, was an effective treatment for subjects with Low- or Intermediate-1-risk MDS, particularly for subjects who had MDS with an associated del 5 (q31-33) cytogenetic abnormality.

Study CC-5013-MDS-003, a multicentre, single-arm, open-label study, evaluated the efficacy and safety of Revlimid^® monotherapy in 148 patients with myelodysplastic syndromes associated with a del (5q) cytogenetic abnormality. In these RBC-transfusion-dependent patients, treatment with Revlimid^® led to significantly improved hematopoiesis thus reducing the need for RBC transfusions.

An 8-week run-in period served as a baseline for each patient's transfusion requirements, and a comparison was subsequently made to a follow-up 8-week period on Revlimid^® to compare transfusion requirements. The bone marrow biopsy and aspirate samples, peripheral blood smear slides and pathology reports for each patient were reviewed centrally by an independent hematologic reviewer. The cytogenetic reports and chromosome prints for each patient were reviewed by an independent cytogenetic reviewer. The well defined baseline characteristics and the hematologic and cytogenetic independent reviews allowed adequate characterization of the treatment effects of Revlimid^® in the targeted population of patients. The primary efficacy endpoint was the proportion of patients who no longer required RBC transfusions. The secondary endpoints were duration of transfusion independence, cytogenetic and pathological responses and safety profile.

Of the 148 patients who were transfusion-dependent at baseline, 67% of the patients achieved transfusion independence, defined as the absence of any RBC transfusion during any consecutive 56 days. Once achieved, the median duration of response was 60 weeks. The median increase in hemoglobin level from minimum at baseline to the maximum level during RBC-transfusion independence was 5.6 g/dL for the transfusion independence responders. Overall, 76.4% of patients achieved a ≥50% decrease in their pretreatment RBC-transfusion requirements during lenalidomide therapy. The median peak hemoglobin concentration among transfusion-free patients was 13.4 g/dL (range 9.2 to 18.6). The response was maintained for at least one year in >60% of the patients who became transfusion-free during the treatment period.

Major cytogenetic responses were observed in 44.2% (53/120) and minor cytogenetic responses were observed in 24.2% (29/120) of the evaluable patients (i.e., those who had at least 20 analyzable metaphases at baseline when using conventional cytogenetic techniques). Improvements in bone marrow morphology were also observed. The secondary efficacy endpoints of change in hemoglobin, bone marrow response, and cytogenetic response provided additional objective measures to confirm the clinical benefit of lenalidomide and to support the primary study endpoint of RBC-transfusion independence.

Results of the single-arm, Phase II, study CC-5013-MDS-003 demonstrated the efficacy of Revlimid^® for the treatment of patients with Low- or Intermediate-1-risk MDS and an associated del 5 (q31-33) cytogenetic abnormality. The treatment benefit of Revlimid^® was based on a surrogate marker of RBC transfusion independence. Additional efficacy data (including Quality of Life data) from adequate well-controlled clinical trials, along with data from a post-market surveillance program is required to quantify the overall magnitude of long-term efficacy. Post-marketing data and a final clinical study report from an ongoing Phase III randomized, double-blind and placebo-controlled study of two doses of Revlimid^® vs. placebo (Study NCT00179621) will be submitted to Health Canada as part of the acceptance of the Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Policy.

3.3.4 Clinical Safety

In the Phase II, multicentre, single-arm, open-label, study CC-5013-MDS-003 (n = 148) the dosing regimen was 10 mg of Revlimid^® once daily, or 10 mg once daily for 21 days every 4 weeks. Treatment was interrupted for adverse effects of Grade 3 and Grade 4 and resumed at a dose of 5 mg per day or 5 mg every other day, according to tolerance, after the adverse effects were resolved. Due to adverse effects, the dose of Revlimid^® was reduced or interrupted at least once in 124 of the 148 (83.8%) patients. The Product Monograph states that the median dose intensity calculated for 124 patients was 4.3 mg lenalidomide per day.

In Study CC-5013-MDS-003, all 148 patients had at least one adverse event (AE), 95.9% of the patients had at least one AE attributed to the study drug, and 92.6% of the patients experienced either Grade 3 or Grade 4 AEs. The most frequently reported AEs were related to blood and lymphatic system disorders (84.5%), skin and subcutaneous tissue disorders (82.4%), gastrointestinal disorders (81.1%), and general disorders and administrative site conditions (79.1%). Neutropenia (63.5%) and thrombocytopenia (62.2%) were the most frequently reported AEs observed. The next most common AEs observed were diarrhea (54.1%), pruritis (43.9%), rash (35.8%) and fatigue (35.8%). The recommended initial dose for lenalidomide is 10 mg daily, and dosing should be continued or modified based upon clinical and laboratory findings.

In the 61.5% patients who developed Grade 3 or Grade 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), with a median time to recovery of 17 days (range, 2-70 days). Grade 3 and Grade 4 thrombocytopenia occurred in 52.7% of the patients at a median of 28 days (range, 8-290 days), with a median duration of 22 days (range, 5-224 days). Risk management includes weekly monitoring of complete blood counts for the first 8 weeks of therapy and at least monthly thereafter; some patients may require use of blood product support and/or growth factors. Patients with platelet counts <50 x 10⁹/L should not be treated with Revlimid^®. A warning has been included in the Product Monograph. Recommendations for dose reduction or interruption of treatment for patients who experience neutropenia or thrombocytopenia are included in the Product Monograph.

At least one serious adverse event (SAE) was reported in 52.0% of the patients. Among the system organ classes, the highest percentages of SAEs were the infections and infestations system organ class (17.6%) and the blood and lymphatic system disorders system organ class (16.2%). Pneumonia (10.1%), neutropenia (6.1%), pyrexia (4.1%), febrile neutropenia (4.1%), thrombocytopenia (4.1%; 6/148), anemia (4.1%; 6/148), and congestive cardiac failure (3.4%) were the most frequently reported SAEs. All other SAEs were reported in <5 patients each.

Thirty-eight out of 148 patients (25.7%) had at least one SAE related to the study drug, and 35/148 (23.6%) had a SAE leading to discontinuation of the study drug. Hematologic toxicities and infections were the most common SAE leading to discontinuation from treatment.

A total of 18.2% of patients received platelet transfusions during the treatment phase of the study. Evidence of bleeding was reported in 7 (25.9%) of the 27 patients at the time of platelet transfusion. Overall, there were nine patients that had 11 bleeding complications that required a platelet transfusion. These bleeding events included Grade 1: epistaxis, ecchymosis, gingival bleeding; Grade 2: epistaxis, rectal hemorrhage, petechiae in one patient each; Grade 3: epistaxis, hematoma in one patient each; and one Grade 4 intestinal perforation at the time of colonoscopy. There were only three Grade 3 /4 bleeding events in this study. No patient discontinued from the study due to bleeding adverse events, and no deaths due to a bleeding adverse event were reported.

There were 12.8% (19/148) events of treatment-emerged neoplastic disease. No data were specifically collected for formal analysis of rates of infection or neoplastic disease.

The increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) was associated with Revlimid^®. Nine out of 148 (6%) patients had a Grade 3 or Grade 4 thromboembolic event (DVT or PE) during treatment with Revlimid^®. The median onset of these events was at 28.1 weeks (min = 3.6 weeks, max = 84.4 weeks). Five patients had thromboembolic events listed as related to study drug. Patients should be carefully observed for signs and symptoms of thromboembolism and advised to seek medical care immediately if they develop shortness of breath, chest pain, or arm/leg swelling.

Due to the fact that lenalidomide is a thalidomide analog, there is the risk of birth defects associated with its use in pregnancy. Revlimid^® should not be used by females who are or may become pregnant. Females of childbearing potential must use at least two methods of birth control. Two simultaneous effective methods of birth control should be used to prevent fetal exposure to the drug. Revlimid^® will only be available through a controlled distribution program (RevAid^SM) to reduce the risk of fetal exposure. Physicians registered with the program, will be required to check pregnancy tests, and Revlimid^® will not be prescribed to any female patient of childbearing potential until verifying that she has had two negative pregnancy tests. A single negative pregnancy test is required for subsequent prescriptions.

Additional safety data is required to confirm the clinical benefit and long-term safety of Revlimid^®. As part of the post-approval commitments, the sponsor has agreed to provide the final study report of the Phase III clinical trial CC-5013-MDS-004, report all serious adverse reactions within 15 days to Health Canada, and submit a Periodic Safety Update Report (PSUR) semi-annually until the conditions of the authorization have changed.

3.3.5 Issues Outstanding

In keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Policy, the sponsor has agreed to provide the following:

• Final study report of the clinical trial CC-5013-MDS-004, a multicentre, randomized, double-blind, placebo-controlled, three-arm, Phase III study of the efficacy and safety of two doses of lenalidomide vs. placebo in RBC transfusion-dependent subjects with Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion of 5q cytogenetic abnormality. This report should include quality of life data in patients treated with lenalidomide.
• Final PK/PD study results of CC-5013-PK-002, a pharmacokinetic and pharmacodynamic study of oral lenalidomide (Revlimid^®) in subjects with Low- or -Intermediate-1-risk myelodysplastic syndromes. This report should include data regarding the bioavailability of lenalidomide in humans as well as data regarding the effect of Revlimid^® on adult and fetal hemoglobin levels using hemoglobin electrophoresis.
• Implementation and maintenance of the Risk Management Program including the RevAid^SM program under the terms agreed upon by both Health Canada and Celgene.

The sponsor has agreed to submit Periodic Safety Update Reports in a manner deemed appropriate by the review division and consistent with E2C ICH Guidelines.

Reports of all serious adverse reactions that occurred in Canada and all serious unexpected adverse reactions that occurred outside of Canada are to be forwarded within 15 days to Health Canada in accordance with the Guidance for Industry: Notice of Compliance with Conditions.