 |
Clinical Trial Result Information
Protocol number
BA16756
Title of Study
Open label, randomized, multicenter, two-arm study to investigate the impact of NeoRecormon® (epoetin beta) treatment on survival, quality of life, outcome of antineoplastic therapy, and anemia in patients with metastatic breast cancer.
Sponsor
Hoffman-La Roche Ltd
Company division
Pharmaceutical
Product name
NeoRecormon
Generic name
epoetin beta
Therapeutic area
Anemia
Clinical study summary
This was an open label, randomized, multicenter, two arm study to compare the effect of NeoRecormon plus chemotherapy, versus chemotherapy alone, in patients with metastatic breast cancer.
Study center(s)
82 centers in Austria, Belgium, Brazil, Denmark, France, Germany, Greece, Hungary, Italy, Mexico, Netherlands, Poland, Spain, Switzerland, Taiwan, Thailand and UK.
Phase of development
III
Objectives
The primary objective of the study was to compare overall survival of patients with metastatic breast cancer receiving chemotherapy and NeoRecormon with those not receiving NeoRecormon.
Secondary objectives were to investigate progression free survival, the correlation between hemoglobin (Hb) and outcome measures and to investigate hemoglobin response rate in both groups. Additionally, the study was designed to compare Hb AUC between the two treatment groups, investigate transfusion or severe anemia avoidance in both groups, evaluate and compare changes from baseline in quality of life (QoL) between the two treatment groups and to investigate the safety profile in each treatment group.
Methodology
Eligible patients were randomized centrally into one of two treatment arms to begin antineoplastic therapy with taxanes and/or anthracyclines and to receive either NeoRecormon (starting dose 30,000 IU sc once weekly) or standard treatment (transfusions as per standard of care) for 24 weeks. Blood pressure, iron parameters, hematology parameters and safety laboratory parameters were assessed at baseline and every 3-4 weeks during the 24 week treatment period. Hematology parameters were also assessed at week 5. Tumor measurement was performed every 6-8 weeks or when progression was suspected. The FACT-An QoL questionnaire was completed at baseline and at intervals during treatment. Patients then entered a follow up phase, during which survival status and tumor progression were assessed, every 3 months after termination of the treatment phase until 24 months after the last patients was enrolled (end of study).
Number of patients (planned/analyzed)
463 enrolled
Diagnosis and main criteria for inclusion
Adult patients (≥18 years old) with evaluable, metastatic M1 breast cancer, an Hb level of <12.9 g/dL and scheduled to start anthracycline- and/or taxane- based chemotherapy.
Test product, dose and mode of administration or test procedure
NeoRecormon (epoetin beta) at a starting dose of 30,000 IU sc once weekly.
Duration of treatment
24 weeks
Reference therapy, dose and mode of administration or reference procedure
Standard treatment (transfusions per standard of care).
Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Overall survival.
Secondary: Progression free survival; correlation between hemoglobin and outcome (PFS and survival); hemoglobin response; time-adjusted hemoglobin AUC; transfusion-free or severe anemia-free survival; QoL (FACT-An questionnaire).
Safety: Adverse events, laboratory test parameters and vital signs.
Statistical methods
Differences in the hemoglobin response rate between the two treatment arms were tested with a two-sided χ² test with Schouten correction. An analysis of covariance for time- and baseline-adjusted hemoglobin AUC between weeks 5-24 was performed. Hematology (hemoglobin and hematocrit) and iron (serum iron, ferritin, calculated TSAT) parameters over time were analysed descriptively.
All oncology related efficacy endpoints such as overall survival, tumor response, progression free survival were tested using a two-sided log rank test at the 5% α-level. In addition univariate and multiple Cox regression analyses were performed.
Summary (efficacy, safety, other results)
Efficacy: During the study, a total of 13.8% of control patients met the sponsor’s predefined criteria for hemoglobin response compared with 68.4% of patients in the NeoRecormon treatment arm (p<0.001). The mean hemoglobin AUC for patients in the control arm of the study was -0.4 compared with a mean AUC of 1.3 for patients receiving NeoRecormon (p<0.0001), this difference becoming apparent as early as 6 weeks into the study. The mean change from baseline in Hb levels was markedly greater in the NeoRecormon treatment arm compared with the control arm (1.5 g/dL vs. 0.1 g/dL, respectively). There were no clinically relevant differences between the treatment groups with respect to the change from baseline to last value in any of the iron parameters assessed during the study.
NeoRecormon treatment was associated with an approximate 50% reduction in the need for blood transfusions during the study (14% vs. 27% patients received a transfusion in the NeoRecormon and control groups, respectively). There was no difference between the study arms with respect to the change from baseline in QoL as assessed by the FACT-An questionnaire. There was no statistically significant difference between the control and NeoRecormon arms with regard to overall survival (log-rank p-value = 0.5221) with a median time to death of 15.5 months in both groups. Univariate and multiple Cox regression robustness analyses provided results consistent with the overall analysis.
There was no statistically significant difference in median time to progression or death between the control (5.4 months) and NeoRecormon (4.9 months) treatment arms (log-rank p-value=0.4472). Furthermore, robustness analyses assessing ‘on-treatment’ progression free survival demonstrated a similar percentage of control (56.9%) and NeoRecormon patients (59.7%) with a progression event during trial treatment or within 30 days after the last dose of trial treatment.
There was an apparent correlation between hemoglobin AUC and survival (p=0.0022) or progression free survival (p=0.344). This finding indicated that patients with a high hemoglobin AUC (high increase over baseline) had an increased survival or progression free survival compared with other patient subgroups.
A greater number of patients in the control arm (27.6%) had transfusion and severe anemic events compared with the NeoRecormon arm (17.3%), reflecting the efficacy of NeoRecormon treatment with respect to preventing transfusion by effective increase in hemoglobin. Time to event analyses demonstrated a statistically significant difference between the two treatment arms (p=0.0088).
A total of 143 patients in the control arm and 152 patients in the NeoRecormon arm had at least one measurable lesion at baseline and were included in the analyses of overall best tumor response. Of these, 41 patients in the control arm and 35 patients in the NeoRecormon arm achieved a tumor response (complete response or partial response).
Safety: Gastrointestinal disorders were the most frequently reported adverse events, being experienced by 58% of patients in the control arm and by 57% of patients in the NeoRecormon treatment arm. The most commonly reported gastrointestinal event was nausea, reported by 35% of NeoRecormon patients and 29% of control patients. Five patients experienced serious adverse events which were considered related to NeoRecormon treatment. Pulmonary embolism and subclavian vein thrombosis were recorded by two patients each and pyrexia was reported in one patient. Gastrointestinal disorders were the main reason for withdrawal, reported by 3% of patients in each treatment arm. Pulmonary embolism (3 patients), deep vein thrombosis (2 patients) and asthenia (2 patients) were the only adverse events leading to NeoRecormon dose modification which were recorded by more than one patient each. A higher percentage of NeoRecormon patients than control patients experienced thromboembolic events (TEEs) during the study (13% vs. 6%) and a shorter time to TEE for the NeoRecormon treatment arm compared with control (p=0.008, log rank test) was seen. However, the percentage of patients who experienced a serious TEE (3% control versus 4% NeoRecormon) or TEE leading to death (2% in each arm) was comparable. A higher percentage of NeoRecormon patients (11%) withdrew prematurely from the study as a result of a TEE compared with patients in the control arm (6%). There were no clinically relevant differences between the treatment groups with respect to laboratory test parameter value abnormalities or vital signs.
Over the treatment and follow up period, the death rate was similar in both the treatment arms. A total of 73% of patients in each arm died during the treatment and follow up period (or within 30 days of the last dose of study treatment). There were no obvious differences between the treatment arms with respect to the reasons for death, the most common being disease progression of the underlying metastatic breast cancer. None of the deaths was considered related to treatment.
Conclusions
Treatment with NeoRecormon 30,000 IU once weekly resulted in a significant increase in Hb in patients with metastatic breast cancer and a Hb at baseline <13 g/dL who were receiving anthracycline- or taxane-based chemotherapy. This study, originally designed to show an improvement in overall survival in patients receiving NeoRecormon compared with patients receiving standard of care (blood transfusions as needed), did not meet its primary study objective but also did not show a negative impact in this patient cohort. There was also no negative impact on progression-free survival but, in line with the finding of a significant reduction of transfusion, a highly significant improvement in transfusion-free survival was seen. No new, unexpected safety findings were observed in this study conducted outside the current label of NeoRecormon. Therefore the results of this study do not change the overall risk/benefit assessment of NeoRecormon within its licensed indications.
Date of report
5/1/2006
Click here for the protocol registry listing of this trial.
|
