Breast Cancer
Conditions
Keywords
Advanced breast cancer, metastatic breast cancer
Brief summary
The purpose of this study is to evaluate the efficacy of a new dose of 500mg Fulvestrant with the standard dose of 250mg in Chinese postmenopausal women with oestrogen receptor positive advanced breast cancer who have failed a prior endocrine treatment.
Detailed description
Fulvestrant, at a dose of 250mg every 28 days, is the first oestrogen receptor antagonist with no agonist effects shown to be at least as effective for both TTP (Time to Progression) and OR (Objective Response) as a third-generation aromatase inhibitor in the second-line treatment of advanced breast cancer (Howell et al 2002, Osborne CK et al 2002).In these studies overall survival was also similar between the fulvestrant and anastrozole treatment arms (Pippen J et al 2003). Fulvestrant has received approval in 70 countries worldwide at this dose regimen. However, evidence from a number of studies suggests that higher dose may be able to enhance efficacy further: * Data from Study 0036 (Addo S et al, 2002) suggested that a dose-response relationship may exist. In female volunteers given a single intramuscular (i.m.) injection of fulvestrant (250mg, 125mg or placebo), there was a dose-dependent inhibition of ethinyloestradiol-induced endometrial thickening seen at Day 28. * Results from short term exposure to fulvestrant in Studies 0002 (DeFriend D et al 1994) and 0018 (Robertson et al 2001) showed that expression of ER, progesterone receptor (PgR) and the cell proliferation-related antigen Ki67 are reduced in a dose-dependent manner. * Data from Studies 0020 (Howell et al 2002) and 0021(Osborne CK et al 2002) suggested that a dose-response effect exists for fulvestrant. Fulvestrant 250mg was shown to be superior to fulvestrant 125mg, which was discontinued as it failed to meet minimum efficacy requirements. * Evidence from pharmacokinetic modelling indicated that fulvestrant 500 mg dose regiment can achieve higher steady state plasma concentrations compared with fulvestrant 250mg and that steady state concentrations can be achieved earlier than with fulvestrant 250mg. * Data from Study CONFIRM (A Di Leo et al 2009), a phase III randomised parallel-group trial, demonstrated that fulvestrant 500mg offers a statistically significant longer TTP compared with fulvestrant 250mg (median TTP: 6.5 months vs. 5.5 months; hazard ratio=0.80 \[95% CI 0.68 to 0.94\]; P=0.006), which seemed to be the consequence of an increase in the rate, and of a prolongation in duration, of disease stabilization. The 50% events overall survival analysis also seemed to favour fulvestrant 500mg, although statistical significance was not reached(hazard ratio=0.84 \[95% CI 0.69 to 1.03\]; P=0.091). The safety analysis did not raise any relevant concerns in relation to fulvestrant 500mg. Therefore, this study will compare Fulvestrant 500mg with fulvestrant 250mg in a Chinese population in order to understand the optimal dose for Chinese patients with breast cancer.
Interventions
DRUGFulvestrant
Fulvestrant was supplied as a castor oil based solution in clear neutral glass pre-filled syringes. Each syringe will contain 250 mg of fulvestrant in 5 ml.
DRUGPlacebo
Matching placebo was supplied as a castor oil based solution in clear neutral glass prefilled syringes. Each syringe will contain 5 ml.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Postmenopausal women defined as a woman who has stopped having menstrual periods * Breast Cancer has continued to grow after having received treatment with an anti-estrogen hormonal treatment such as tamoxifen or an aromatase inhibitor * Requiring hormonal treatment * Oestrogen-receptor positive tumour * Written informed consent to participate in the trial
Exclusion criteria
* Treatment with an investigational or non-approved drug within one month * An existing serious disease, illness, or condition that will prevent participation or compliance with study procedures * A history of allergies to any active or inactive ingredients of fulvestrant (i.e. castor oil) * Treatment with more than one regimen of chemotherapy for advanced breast cancer * Treatment with more than one regimen of hormonal treatment for advanced breast cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 36 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or unequivocal progression of existing non-target lesions, or the appearance of new lesions, or death (by any cause in the absence of progression). The primary analysis for PFS was the log rank test stratified by last endocrine therapy received prior to fulvestrant (AO vs. AI). The treatment effect was estimated using the HR of 500 mg fulvestrant to 250 mg fulvestrant together with the corresponding 95% CI and p value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 36 months | The ORR is defined as the proportion of all randomized patients with measurable disease at baseline who have a best objective tumour response of either CR or PR per RECIST v1.1. |
| Clinical Benefit Rate | 36 months | A clinical benefit (CB) responder is defined as a patient having a best overall response of either CR, PR or SD for at least 24 weeks per RECIST v1.1. As tumour assessments can occur ± 2 weeks of the specified time point, the CBR is defined as the proportion of patients in the FAS who have CB ≥ 22 weeks (or 154 days). |
| Duration of Response | 36 months | Duration of response (DoR) will be evaluated only for patients who have an objective response, and is defined as the time from the date of first documentation of objective response (i.e., the initial visit at which CR or PR was recorded) until the date of disease progression or death due to any cause (whichever is earlier). The time of the initial response will be defined as the latest of the dates contributing towards the first visit response of PR or CR. Any patient who has not progressed or died by the date of DCO, or who has been lost to follow up, will be right-censored at the date of their last disease assessment. |
| Duration of Clinical Benefit | 36 months | Duration of clinical benefit (DoCB) will be evaluated only for patients who have CB, and is defined as the time from the date of randomisation until the date of disease progression or death from any cause, whichever is earlier. Any patient who has not progressed or died by the date of DCO or who has been lost to follow up will be right censored at the date of their last evaluable disease assessment. |
Countries
China
Participant flow
Recruitment details
The planned population size was 220 randomised patients. 249 patients were enrolled with 28 screen-failured patients and altogether 221 patients were randomised. The recuitment period of this study took 34 months, first subject in on 01 Mar 2011 and last subject in on 23 Dec 2013.
Pre-assignment details
The Enrollment number in the protocol section means the number of patients enter the trial and receiving screening procedure, the number of participants Started in the Participant Flow module means the number of randomized patients and do not include screening failure patients.
Participants by arm
| Arm | Count |
|---|---|
| Fulvestrant 500 mg Fulvestrant 500 mg intramuscular (im) every 28 (± 3) days plus an additional 500 mg on Day 15 (± 3) of first month only | 111 |
| Fulvestrant 250 mg Fulvestrant 250 mg im every 28 (± 3) days | 110 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Did not receive treatment | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Ongoing treatment at data cut-off | 27 | 23 |
| Overall Study | Withdrawal by Subject | 7 | 10 |
Baseline characteristics
| Characteristic | Fulvestrant 500 mg | Fulvestrant 250 mg | Total |
|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 10.12 | 53.1 years STANDARD_DEVIATION 10.22 | 53.3 years STANDARD_DEVIATION 10.15 |
| Age, Customized ≥50 to <65 Years | 61 participants | 56 participants | 117 participants |
| Age, Customized <50 Years | 37 participants | 40 participants | 77 participants |
| Age, Customized ≥65 Years | 13 participants | 14 participants | 27 participants |
| Extent of disease at baseline Locally advanced breast cancer only | 1 participants | 1 participants | 2 participants |
| Extent of disease at baseline Metastatic disease | 110 participants | 109 participants | 219 participants |
| Race/Ethnicity, Customized Asian | 111 Participants | 110 Participants | 221 Participants |
| Sex: Female, Male Female | 111 Participants | 110 Participants | 221 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 61.0 kg | 60.5 kg | 60.7 kg |
| WHO Performance Status (0) Normal activity | 80 participants | 77 participants | 157 participants |
| WHO Performance Status (1) Restricted activity | 28 participants | 30 participants | 58 participants |
| WHO Performance Status (2) In bed ≤50% of the time | 3 participants | 3 participants | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 68 / 109 | 65 / 110 |
| serious Total, serious adverse events | 4 / 109 | 9 / 110 |
Outcome results
Primary
Progression-free Survival
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or unequivocal progression of existing non-target lesions, or the appearance of new lesions, or death (by any cause in the absence of progression). The primary analysis for PFS was the log rank test stratified by last endocrine therapy received prior to fulvestrant (AO vs. AI). The treatment effect was estimated using the HR of 500 mg fulvestrant to 250 mg fulvestrant together with the corresponding 95% CI and p value.
Time frame: 36 months
Population: FAS: all randomised patients and compared the treatment groups on the basis of randomised treatment, regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant 500 mg | Progression-free Survival | 8.0 months |
| Fulvestrant 250 mg | Progression-free Survival | 4.0 months |
Comparison: The results of this study would be considered to be consistent with that of the CONFIRM study if the hazard ratio (HR) point estimate for the treatment comparison was \<1 (ie, it favoured fulvestrant 500 mg), without the requirement for the benefit of fulvestrant 500 mg to be statistically significant.p-value: 0.07895% CI: [0.54, 1.03]Log Rank
Secondary
Clinical Benefit Rate
A clinical benefit (CB) responder is defined as a patient having a best overall response of either CR, PR or SD for at least 24 weeks per RECIST v1.1. As tumour assessments can occur ± 2 weeks of the specified time point, the CBR is defined as the proportion of patients in the FAS who have CB ≥ 22 weeks (or 154 days).
Time frame: 36 months
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant 500 mg | Clinical Benefit Rate | 53 patients |
| Fulvestrant 250 mg | Clinical Benefit Rate | 36 patients |
p-value: 0.02395% CI: [1.04, 1.8]Regression, Logistic
Secondary
Duration of Clinical Benefit
Duration of clinical benefit (DoCB) will be evaluated only for patients who have CB, and is defined as the time from the date of randomisation until the date of disease progression or death from any cause, whichever is earlier. Any patient who has not progressed or died by the date of DCO or who has been lost to follow up will be right censored at the date of their last evaluable disease assessment.
Time frame: 36 months
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant 500 mg | Duration of Clinical Benefit | 14.3 months |
| Fulvestrant 250 mg | Duration of Clinical Benefit | 13.8 months |
Secondary
Duration of Response
Duration of response (DoR) will be evaluated only for patients who have an objective response, and is defined as the time from the date of first documentation of objective response (i.e., the initial visit at which CR or PR was recorded) until the date of disease progression or death due to any cause (whichever is earlier). The time of the initial response will be defined as the latest of the dates contributing towards the first visit response of PR or CR. Any patient who has not progressed or died by the date of DCO, or who has been lost to follow up, will be right-censored at the date of their last disease assessment.
Time frame: 36 months
Population: Evaluable for Response Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant 500 mg | Duration of Response | 16.6 months |
| Fulvestrant 250 mg | Duration of Response | 22.2 months |
Secondary
Objective Response Rate
The ORR is defined as the proportion of all randomized patients with measurable disease at baseline who have a best objective tumour response of either CR or PR per RECIST v1.1.
Time frame: 36 months
Population: Evaluable for Response Set, included all patients in the FAS with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fulvestrant 500 mg | Objective Response Rate | 16 patients |
| Fulvestrant 250 mg | Objective Response Rate | 11 patients |
p-value: 0.10795% CI: [0.93, 2.24]Regression, Logistic