Product: Darbepoetin alfa Clinical Study Report: Date: 22 August 2007 Page 2 of 14145

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1 Date: 22 ugust 2007 Page 2 of SYNOPSIS Name of Sponsor: mgen Inc., Thousand Oaks, C, US Name of Finished Product: ranesp Name of ctive Ingredient: Darbepoetin alfa Title of Study: Randomized, Double Blind, Placebo-Controlled Study of Subjects With Previously Untreated Extensive-Stage Small-Cell Lung Cancer (SCLC) Treated With Platinum plus Etoposide Chemotherapy with or without darbepoetin alfa Investigator(s) and Study Center(s): This study was conducted at 69 sites in Europe, ustralia, and Canada. complete list of investigators and sites is provided in ppendix 4. Publication(s): None as of the date of this report. Study Period: 10 December 2002 (date first subject was randomized) through 22 February 2007 (data cutoff date) Development Phase: 3 Introduction and Objectives: The primary objective of this study was to evaluate whether increasing or maintaining hemoglobin concentrations with darbepoetin alfa, when administered with platinum-containing chemotherapy in subjects with previously untreated extensive-stage SCLC, increases survival. The secondary objective of this study was to evaluate whether darbepoetin alfa improves Functional ssessment of Cancer Therapy Fatigue (FCT-Fatigue) subscale scores. Other objectives were to assess the effect of darbepoetin alfa on subject symptom assessment, progression-free survival, time to progression, tumor response, duration of tumor response, RBC transfusions, and FCT-General subscale scores, and to assess the overall safety profile of darbepoetin alfa in subjects with previously untreated extensive-stage SCLC. Methodology: This was a multicenter, randomized, double-blind, placebo-controlled study to assess the effect of darbepoetin alfa on survival in subjects with previously untreated extensive-stage SCLC receiving platinum and etoposide chemotherapy. Eligible subjects were randomized in a 1:1 ratio to receive darbepoetin alfa or placebo throughout 6 cycles of chemotherapy and for 3 weeks after the last dose of on-study chemotherapy. Randomization was stratified by region (Western Europe, ustralia/north merica, and rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2), and lactate dehydrogenase (LDH; below versus above the upper limit of normal). Darbepoetin alfa was administered at a dose of 300 µg once weekly (QW) for the first 4 weeks, followed by 300 µg once every 3 weeks (Q3W) for the remainder of the treatment period. During study weeks where no dose was planned, an additional weekly dose of investigational product was to be administered if a subject s hemoglobin concentration was < 11.0 g/dl. Investigational product was to be withheld if a subject had a hemoglobin concentration 14.0 g/dl and reinstated once the concentration was < 13.0 g/dl. Subjects were to have follow-up visits every 3 months after their end-of-study treatment visit until death or until 496 deaths had occurred (End of Study). Those subjects still alive at the End of Study entered the long-term follow-up period and were to be followed until death.

2 Date: 22 ugust 2007 Page 3 of Number of Subjects Planned: pproximately 600 subjects (300 darbepoetin alfa, 300 placebo) were planned. Number of Subjects Enrolled: total of 600 subjects were randomized, and 596 (99.5%) received at least 1 dose of chemotherapy and investigational product. Sex: 385 men (65%), 211 women (35%) Mean (SD) ge: 61.0 (8.8) years Ethnicity (Race): 596 white (100%) Diagnosis and Main Criteria for Eligibility: Subjects of legal age to give consent with pathologically proven extensive-stage SCLC who planned to receive chemotherapy with carboplatin or cisplatin plus etoposide Q3W for 6 cycles were eligible for this study after giving written informed consent. Subjects were required to have a hemoglobin concentration 9.0 g/dl and 13.0 g/dl, an ECOG status of 0 to 2, and a life expectancy of 3 months. Subjects were also required to have adequate liver, renal, and hematopoietic function (absolute neutrophil count 1.5 x 10 9 /L and platelet count 100 x 10 9 /L). Subjects were excluded from the study if they had received previous chemotherapy for SCLC, previous radiotherapy (except as symptom palliation for bone or brain lesions 24 hours before randomization), > 2 units of packed RBCs within 4 weeks or any RBC transfusion within 2 weeks of randomization, or recombinant human erythropoietin or darbepoetin alfa within 4 weeks of randomization. Other exclusion criteria included brain metastases that were symptomatic or treated with steroids, other known primary malignancies within the past 5 years (except basal cell carcinoma, squamous cell carcinoma in situ, cervical carcinoma, or surgically cured malignancies), cardiac diseases, iron deficiency, or known primary hematologic disorders that could cause anemia. Investigational Product, Dose and Mode of dministration, Manufacturing Batch Number: Darbepoetin alfa was administered SC at a dose of 300 µg QW or Q3W. Darbepoetin alfa was provided at a concentration of 500 µg/ml in vials containing approximately 1.0 ml of a human serum albumin-free polysorbate formulation. Fill lot numbers are provided in ppendix 18. Duration of Treatment: Darbepoetin alfa or placebo was administered for up to 24 weeks. Reference Therapy, Dose and Mode of dministration, Manufacturing Batch Number: Placebo was provided in containers identical to darbepoetin alfa and was administered SC at the same schedule (ie, QW or Q3W). Fill lot numbers are provided in ppendix 18. Study Endpoints Primary Endpoint: The co-primary endpoints of the study were change in hemoglobin concentration from baseline to the end of the chemotherapy treatment period (EOCP) and survival time, which were tested in a step-down manner. Survival time was only to be tested if the mean change in hemoglobin concentration endpoint was statistically significant at the level. Secondary Efficacy Endpoint: The secondary efficacy endpoint was the change in FCT-Fatigue subscale score from baseline to the end of study treatment (EOST).

3 Date: 22 ugust 2007 Page 4 of Other Efficacy Endpoints: progression-free survival best overall response, defined as complete response, partial response, stable disease, or progressive disease as per Response Evaluation Criteria in Solid Tumors (RECIST) objective tumor response duration of tumor response time to progression incidence and number of units of red blood cells (RBCs) transfused during study treatment change in patient-reported outcomes (PRO) from baseline to week 7, week 13, and EOST change in hemoglobin from baseline to week 19 and EOST proportion of subjects in each treatment group reaching a hemoglobin concentration of 12 g/dl at any point amount of time (weeks) that subjects in each treatment group spent with a hemoglobin concentration > 12 g/dl proportion of subjects in each group with a hemoglobin concentration > 12 g/dl for 50% of the entire treatment period Statistical Methods: Change in hemoglobin from baseline to the EOCP, a co-primary endpoint, was evaluated using the primary analysis set and was compared between treatment groups using a generalized Cochran-Mantel-Haenszel (CMH) test (also known as the Wilcoxon rank sum test) adjusted for stratification factors (region, ECOG performance status, and LDH). n analysis of variance (NOV) was conducted, and the adjusted (least square) means and 95% CIs were provided for each treatment group and the treatment difference. The NOV model included treatment group and the stratification factors. If the change in hemoglobin endpoint was statistically significant at the level, then the survival endpoint was to be tested. Between-group differences were evaluated using a log-rank test stratified by region, ECOG performance status, and LDH to compare the survival functions between the 2 treatment groups. The Kaplan-Meier estimates of the survival functions for each treatment group were also provided. The hazard ratio and corresponding 95% CI were calculated using a stratified Cox proportional hazards regression model with treatment as a factor, stratified by region, ECOG, and LDH. Time to disease progression and progression-free survival were evaluated using the same methods as those used to evaluate survival. Summary statistics were provided for all other endpoints. The change in FCT-Fatigue subscale score from baseline to the EOST was analyzed by an analysis of covariance (NCOV) model including the stratification factors and baseline FCT-Fatigue subscale score. Treatment-emergent adverse events were grouped by system organ class and preferred term according to the MedDR 9 dictionary. Table summarizing the subject incidence of all adverse events, serious adverse events (including fatal events), severe adverse events, treatment-related adverse events, treatment-related serious adverse events, and treatment-related severe adverse events were provided. Summary statistics were provided for all other safety endpoints.

4 Date: 22 ugust 2007 Page 5 of Summary of Results: Subject Disposition: total of 705 subjects were screened for participation in this study and 600 were randomized. Of these randomized subjects, 597 (99.5%) received at least 1 dose of investigational product (darbepoetin alfa or placebo) and 596 (99.3%) received at least 1 dose of investigational product and chemotherapy. Overall, 305 subjects (51%) completed the study as determined by the investigator (50% darbepoetin alfa, 52% placebo). The most frequently reported reasons for study discontinuation were disease progression (19% darbepoetin alfa, 16% placebo) and death (16% in both treatment groups). Efficacy Results: Darbepoetin alfa effectively lessened the reduction in hemoglobin concentrations relative to placebo in subjects with previously untreated extensive-stage SCLC receiving cytotoxic chemotherapy. The mean difference (95% CI) between darbepoetin alfa and placebo with respect to the change in hemoglobin from baseline to EOCP was 0.84 g/dl (0.53 g/dl, 1.15 g/dl). The difference between treatment groups for the change in hemoglobin from baseline to EOCP was statistically significant (p < 0.001) based on the CMH statistic adjusting for the stratification factors (primary analysis). No difference in overall survival was observed between the darbepoetin alfa and placebo groups. Median survival time (time to death) was 40 weeks for both groups, and the hazard ratio (darbepoetin alfa/placebo) was 0.93 (95% CI: 0.78, 1.11). The upper limit of the 95% CI excludes an increase in risk of > 11% for subjects receiving darbepoetin alfa relative to those receiving placebo with 95% confidence. Similarly, no difference in progression-free survival (hazard ratio 1.02; 95% CI: 0.86, 1.21) or time to disease progression or death due to disease progression (hazard ratio 1.03; 95% CI: 0.86, 1.23) was observed between treatment groups. Darbepoetin alfa was associated with a significantly lower risk of RBC transfusions from week 1 to the EOST compared with placebo (hazard ratio 0.40; 95% CI: 0.29, 0.55). Patient-reported Outcome Results: The mean change in FCT-Fatigue subscale score from baseline to the EOST was 1.5 points for the darbepoetin alfa group and 0.7 points for the placebo group, a difference of 0.86 (95% CI: -1.16, 2.88) based on the NCOV adjusted for stratification factors (baseline ECOG performance status and baseline LDH) and baseline FCT-Fatigue. Safety Results: lmost all subjects had at least 1 adverse event during the study (96% darbepoetin alfa, 98% placebo). The subject incidence of treatment-related adverse events was 5% in each group. Serious adverse events were reported for 46% of subjects in the darbepoetin alfa group and 41% of subjects in the placebo group; the most frequently reported serious adverse events were related to the underlying malignancy. Few of these subjects had treatment-related serious adverse events (2% darbepoetin alfa, 1% placebo). The most frequently reported treatmentrelated serious adverse event was pulmonary embolism (1% darbepoetin alfa, 0% placebo). similar percentage of subjects discontinued the study because of adverse events (4% darbepoetin alfa, 3% placebo). Eighteen percent of subjects in the darbepoetin alfa group and 16% of subjects in the placebo group died during the study treatment period or within 30 days after the last dose of investigational product. Two deaths in the darbepoetin alfa group (pulmonary embolism and ischemic stroke) were considered to have a reasonable possibility of being treatment related by the investigator. Cardiovascular and thromboembolic events occurred at a moderately higher rate in the darbepoetin alfa group (22%) compared to the placebo group (15%), primarily due to embolisms/thromboses (9% darbepoetin alfa, 5% placebo). During the study treatment period, deaths reported by the investigator as resulting from cardiovascular/thromboembolic events did not differ between treatment groups (4% darbepoetin alfa, 3% placebo).

5 Date: 22 ugust 2007 Page 6 of No subject in either treatment group had neutralizing anti-darbepoetin alfa antibodies. Conclusions: In this phase 3 study, darbepoetin alfa administered as a fixed dose of 300 µg QW followed by 300 µg Q3W significantly lessened reductions in hemoglobin concentrations relative to placebo in subjects with previously untreated extensive-stage SCLC receiving cytotoxic chemotherapy. Superiority of darbepoetin alfa versus placebo was not demonstrated for overall survival, with no difference observed between the treatment groups (hazard ratio 0.93; 95% CI: 0.78, 1.11). Thromboembolic events occurred at a moderately higher rate in subjects receiving darbepoetin alfa than in those receiving placebo, consistent with the known safety profile of darbepoetin alfa in chemotherapy induced anemia. In summary, a favorable risk/benefit ratio for darbepoetin alfa in the setting of chemotherapy-induced anemia was observed in this study.