Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study. 
Hormone receptor-positive breast cancer is treated with estrogen inhibitors.  Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER.  Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists.  Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors.  This randomized Phase II study evaluated cediranib plus fulvestrant.  Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible.  The primary endpoint was progression-free survival (PFS).  Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK).  Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant.  Demographic/baseline characteristics were well balanced.  Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant.  CBR was 42 % in both arms.  The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %).  The incidence of grade ≥ 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm.  There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK.  Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated.  Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.