Comparing the Efficacy and Tolerability of Fulvestrant 500 mg Versus 250 mg in Advanced Breast Cancer Women
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||A Randomised, Double-Blind, Parallel-Group, Multicentre Study Comparing the Efficacy and Tolerability of Fulvestrant 500 mg Versus 250 mg in Postmenopausal Women With ER+ Advanced Breast Cancer Progressing or Relapsing After Previous Endocrine Therapy|
- Progression-free survival (PFS) [ Time Frame: RECIST 1.1 tumour assessments carried out every 12 weeks (+/- 2 weeks) from randomisation until disease progression ] [ Designated as safety issue: No ]To compare the efficacy of fulvestrant 500 mg treatment with fulvestrant 250 mg treatment in terms of progression-free survival.
- CL/F, Vss/F, Cmax, tmax, Cmin, AUC0-t and t1/2 [ Time Frame: Randomisation to week 12 ] [ Designated as safety issue: No ]To describe the pharmacokinetic profile of fulvestrant 500mg and fulvestrant 250 mg
- Objective Response Rate [ Time Frame: whole study period ] [ Designated as safety issue: No ]To compare the objective response rate of patients treated with fulvestrant 500 mg with the objective response rate of patients treated with fulvestrant 250 mg
- Clinical Benefit Rate [ Time Frame: whole study period ] [ Designated as safety issue: No ]To compare clinical benefit rate of patients treated with fulvestrant 500 mg with the clinical benefit rate of patients treated with fulvestrant 250 mg
- Duration of Response (DoR) [ Time Frame: whole study period ] [ Designated as safety issue: No ]To estimate the duration of response of patients treated with fulvestrant 500 mg and fulvestrant 250 mg
- Duration of Clinical Benefit (DoCB) [ Time Frame: whole study period ] [ Designated as safety issue: No ]To estimate the duration of clinical benefit of patients treated with fulvestrant 500 mg and fulvestrant 250 mg
- Frequency and Severity of Adverse Events [ Time Frame: whole study period ] [ Designated as safety issue: Yes ]To assess the tolerability of fulvestrant 500 mg treatment compared with fulvestrant 250 mg treatment
|Study Start Date:||March 2011|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
Experimental: Fulvestrant 500mg
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
Other Name: Faslodex
Active Comparator: Fulvestrant 250mg / matching placebo
Fulvestrant 250mg (1 syringe of fulvestrant 250mg + 1 syringe matching placebo)
Drug: Fulvestrant /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
Other Name: Faslodex
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.
|Hefei, Anhui, China|
|Dalian, Liaoning, China|
|Taiyuan, Shanxi, China|
|Kunming, Yunnan, China|
|Principal Investigator:||Zefei Jiang||307 Hospital of PLA|
|Study Director:||Yuri E Rukazenkov||AstraZeneca|