Fulvestrant 500 mg vs 250 mg in CONFIRM Trial
Fulvestrant 500 mg vs 250 mg in CONFIRM Trial
The CONFIRM study design, including eligibility criteria, exclusion criteria, and the calculation of sample size, has been described in detail elsewhere. Briefly, CONFIRM was a randomized, phase III, double-blind trial that evaluated two different doses of fulvestrant (500mg vs 250mg) in postmenopausal patients who had either locally advanced or metastatic ER-positive breast cancer (ClinicalTrials.gov identifier: NCT00099437; http://www.clinicaltrials.gov/ct2/show/NCT00099437). The primary study endpoint was PFS (the time elapsing between the date of randomization and the date of earliest evidence of objective disease progression or death from any cause). Secondary endpoints included objective response rate, clinical benefit rate, duration of response, duration of clinical benefit, OS, tolerability, and quality of life.
After initial analysis, all patients, regardless of whether they were still receiving randomized treatment, entered a survival follow-up phase. Patients remaining on randomized treatment during this follow-up phase continued on blinded randomized treatment until progression and were assessed for serious adverse events (SAEs) and survival status. Patients who had discontinued randomized treatment were assessed for their survival status and best response to their first subsequent systemic breast cancer therapy received after treatment discontinuation.
The study was performed in accordance with the Declaration of Helsinki, consistent with International Conference on Harmonisation/Good Clinical Practice requirements. All patients gave written informed consent before study entry, and the study protocol was approved by the institutional review board of each participating institution.
Patients were randomly assigned to treatment in balanced blocks using a computer-generated randomization schedule; all study personnel were blinded to randomized treatment. Eligible patients were randomly assigned 1:1 to either fulvestrant 500mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (± 3) days thereafter or fulvestrant 250mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28, and every 28 (± 3) days thereafter.
Fulvestrant was supplied in the form of a single dose in a prefilled syringe. Each active prefilled syringe contained 250mg of fulvestrant at a concentration of 50mg/mL in a volume of 5mL, designated fulvestrant 5% weight/volume injection. The placebo prefilled syringe was identical to the active prefilled syringe and also had a volume of 5mL.
OS was defined as the number of days from randomization to death from any cause. Patients who died after the data cutoff or who were known to be alive after the data cutoff were right-censored at the date of the data cutoff. Patients who were last known to be alive before the data cutoff or who were lost to follow-up before the data cutoff were right-censored at the date they were last known to be alive.
After the initial analysis, patients on fulvestrant 250mg were permitted to switch to 500mg before entering the survival follow-up phase. Irrespective of whether they were still receiving randomized treatment, all patients in the follow-up phase continued to have their survival status monitored every 12±2 weeks until cutoff for the final 75% OS analysis (October 31, 2011).
Details of the first subsequent systemic breast cancer therapy received after discontinuation of randomized treatment, and of the best response (complete response, partial response, stable disease, progressive disease, not evaluable) to this therapy were collected.
SAEs were reported to the Patient Safety Database and collated during the survival follow-up phase for those patients still receiving randomized treatment.
OS was first analyzed in 2009, in parallel with the primary analysis of PFS, after the proportion of reported deaths exceeded 50% of the total number of patients randomized across the two treatment groups. The analysis was performed using an unadjusted log-rank test. An additional exploratory analysis, which used a Cox proportional hazards model adjusting for six predefined covariables (age at baseline, response to last endocrine therapy received before fulvestrant, receptor status at diagnosis, visceral involvement at baseline, last therapy before fulvestrant, and measurable disease at baseline) was also performed to assess the robustness of the unadjusted OS result.
An updated analysis is presented here of more mature survival data, performed after the proportion of reported deaths exceeded 75% of the total number of patients randomized across the two treatment groups. The data were analyzed using log-rank statistics, confirmed by Cox proportional hazards model, and summarized by the method of Kaplan–Meier. P values presented are nominal without adjustment for multiplicity, and no alpha was retained for this analysis (the 5% error was used at the initial OS analysis). All statistical tests were two-sided.
For SAEs, summaries and analyses were prepared according to the treatment actually received.
Methods
Study Design and Patients
The CONFIRM study design, including eligibility criteria, exclusion criteria, and the calculation of sample size, has been described in detail elsewhere. Briefly, CONFIRM was a randomized, phase III, double-blind trial that evaluated two different doses of fulvestrant (500mg vs 250mg) in postmenopausal patients who had either locally advanced or metastatic ER-positive breast cancer (ClinicalTrials.gov identifier: NCT00099437; http://www.clinicaltrials.gov/ct2/show/NCT00099437). The primary study endpoint was PFS (the time elapsing between the date of randomization and the date of earliest evidence of objective disease progression or death from any cause). Secondary endpoints included objective response rate, clinical benefit rate, duration of response, duration of clinical benefit, OS, tolerability, and quality of life.
After initial analysis, all patients, regardless of whether they were still receiving randomized treatment, entered a survival follow-up phase. Patients remaining on randomized treatment during this follow-up phase continued on blinded randomized treatment until progression and were assessed for serious adverse events (SAEs) and survival status. Patients who had discontinued randomized treatment were assessed for their survival status and best response to their first subsequent systemic breast cancer therapy received after treatment discontinuation.
Ethics
The study was performed in accordance with the Declaration of Helsinki, consistent with International Conference on Harmonisation/Good Clinical Practice requirements. All patients gave written informed consent before study entry, and the study protocol was approved by the institutional review board of each participating institution.
Randomization and Masking
Patients were randomly assigned to treatment in balanced blocks using a computer-generated randomization schedule; all study personnel were blinded to randomized treatment. Eligible patients were randomly assigned 1:1 to either fulvestrant 500mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (± 3) days thereafter or fulvestrant 250mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28, and every 28 (± 3) days thereafter.
Fulvestrant was supplied in the form of a single dose in a prefilled syringe. Each active prefilled syringe contained 250mg of fulvestrant at a concentration of 50mg/mL in a volume of 5mL, designated fulvestrant 5% weight/volume injection. The placebo prefilled syringe was identical to the active prefilled syringe and also had a volume of 5mL.
Survival Analysis
OS was defined as the number of days from randomization to death from any cause. Patients who died after the data cutoff or who were known to be alive after the data cutoff were right-censored at the date of the data cutoff. Patients who were last known to be alive before the data cutoff or who were lost to follow-up before the data cutoff were right-censored at the date they were last known to be alive.
After the initial analysis, patients on fulvestrant 250mg were permitted to switch to 500mg before entering the survival follow-up phase. Irrespective of whether they were still receiving randomized treatment, all patients in the follow-up phase continued to have their survival status monitored every 12±2 weeks until cutoff for the final 75% OS analysis (October 31, 2011).
Best Response to First Subsequent Therapy
Details of the first subsequent systemic breast cancer therapy received after discontinuation of randomized treatment, and of the best response (complete response, partial response, stable disease, progressive disease, not evaluable) to this therapy were collected.
Tolerability
SAEs were reported to the Patient Safety Database and collated during the survival follow-up phase for those patients still receiving randomized treatment.
Statistical Analysis
OS was first analyzed in 2009, in parallel with the primary analysis of PFS, after the proportion of reported deaths exceeded 50% of the total number of patients randomized across the two treatment groups. The analysis was performed using an unadjusted log-rank test. An additional exploratory analysis, which used a Cox proportional hazards model adjusting for six predefined covariables (age at baseline, response to last endocrine therapy received before fulvestrant, receptor status at diagnosis, visceral involvement at baseline, last therapy before fulvestrant, and measurable disease at baseline) was also performed to assess the robustness of the unadjusted OS result.
An updated analysis is presented here of more mature survival data, performed after the proportion of reported deaths exceeded 75% of the total number of patients randomized across the two treatment groups. The data were analyzed using log-rank statistics, confirmed by Cox proportional hazards model, and summarized by the method of Kaplan–Meier. P values presented are nominal without adjustment for multiplicity, and no alpha was retained for this analysis (the 5% error was used at the initial OS analysis). All statistical tests were two-sided.
For SAEs, summaries and analyses were prepared according to the treatment actually received.
