A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14)

Abstract Background In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ET A -receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. Methods In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175mg/m 2 iv followed by carboplatin iv (AUC 5) on day 1 of every 3-weekcycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. Results A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0months, respectively; HR=1.46, [80% CI: 1.10–1.94]; P =0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: −16%; paclitaxel: −14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43–48% of patients). Conclusions Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.