Comparing the Efficacy and Tolerability of Fulvestrant 500 mg Versus 250 mg in Advanced Breast Cancer Women

Phase 3

Completed

Conditions: Breast Cancer

Interventions: Drug: Fulvestrant
Drug: Placebo

Registration Number: NCT01300351

Lead Sponsor: AstraZeneca

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 249

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fulvestrant 250mg	Placebo	Fulvestrant 250mg (1 syringe of fulvestrant 250mg + 1 syringe matching placebo), Fulvestrant 250 mg and matching placebo i.m. every 28 (+/- 3) days plus an additional 2 placebo syringes on day 14 (+/-3) of first month only
Fulvestrant 250mg	Fulvestrant	Fulvestrant 250mg (1 syringe of fulvestrant 250mg + 1 syringe matching placebo), Fulvestrant 250 mg and matching placebo i.m. every 28 (+/- 3) days plus an additional 2 placebo syringes on day 14 (+/-3) of first month only
Fulvestrant 500mg	Fulvestrant	Fulvestrant 500mg (2 syringes of Fulvestrant 250mg), Fulvestrant 500 mg i.m. every 28 (+/- 3) days plus an additional 500 mg on day 14 (+/-3) of first month only

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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).