Cediranib in Combination with Fulvestrant in Hormone-Sensitive Metastatic Breast Cancer: A Phase II Randomized Study.
Authors: Hyams D. , de Oliveira C. , Snyder R. , Klein P. , Vinholes J. , Audeh M. , Alencar V. , Lombard J. , Mookerjee B. , Xu J. , Chan A. 
Published: December 2010

Abstract
Background: Cediranib (RECENTIN™) is a highly potent VEGF signaling inhibitor that has shown clinical activity across a range of tumors at doses of 20, 30 and 45 mg, both as monotherapy and in combination with other agents. Fulvestrant (FASLODEX™) is a selective estrogen-receptor antagonist with no agonist effects that is effective in patients (pts) with hormone-sensitive, postmenopausal metastatic breast cancer (MBC) who have progressed or recurred on prior hormonal therapy. This randomized screening study evaluated cediranib in combination with fulvestrant.Methods: Eligible pts were postmenopausal women with histologically/cytologically confirmed hormone-sensitive MBC with measurable or non-measurable disease, no prior anti-VEGF or fulvestrant treatment and ≤1 prior cytotoxic chemotherapy. Pts received once-daily oral cediranib 45 mg or placebo, both in combination with fulvestrant (loading dose schedule: 500 mg im [2 x 250 mg] on day 1, 250 mg im on day 14, then 250 mg im every month). The primary objective was to determine whether cediranib + fulvestrant prolonged progression-free survival (PFS) vs placebo + fulvestrant (≥80% power to detect a hazard ratio [HR] of 0.50; P&lt;0.2). Secondary assessments included objective response rate (complete response [CR] + partial response [PR]; only pts with measurable disease at baseline), duration of response (DoR), clinical benefit rate (CR + PR + stable disease ≥6 months), determination of any pharmacokinetic interaction, safety and tolerability.Results: Sixty-two pts were randomized to cediranib + fulvestrant (n=31) or placebo + fulvestrant (n=31). Baseline characteristics were balanced between arms with a median of 2 prior hormonal therapies in each arm. PFS in pts treated with cediranib + fulvestrant showed a numerical advantage vs placebo + fulvestrant that was not statistically significant (HR 0.867; 95% CI 0.450–1.669; P=0.669). The objective response rate was 22% (n=4 PRs; median DoR=208 days) for cediranib + fulvestrant vs 8% (n=1 PR; DoR =224 days) for placebo + fulvestrant. The clinical benefit rate was 42% (n=13) in both arms. There was no evidence of a clinically relevant effect of cediranib on the pharmacokinetics of fulvestrant. The most common adverse events (AEs) in pts receiving cediranib + fulvestrant were diarrhea (68%), fatigue (61%) and hypertension (55%). The cediranib + fulvestrant arm showed a higher incidence of CTCAE grade ≥3 AEs (68% vs 32%), serious AEs (48% vs 13%), AEs leading to discontinuation of cediranib/placebo (39% vs 10%), and cediranib/placebo dose reductions or pauses (74% vs 32%). No new unexpected toxicities or clinical laboratory findings were observed with cediranib + fulvestrant and the AE profile was consistent with previous studies of cediranib 45 mg. There were two deaths in the placebo + fulvestrant arm during the study: sepsis from a leg ulcer, and respiratory failure in a pt with pulmonary metastases, emphysema and pleural effusion.Conclusions: Cediranib 45 mg + fulvestrant 250 mg demonstrated clinical activity in MBC but cediranib did not appear to be sufficiently well tolerated at this dose. Future studies of cediranib in this setting should be considered using lower doses in combination with hormonal agents/chemotherapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 204.