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).
Author(s): Cognetti F(1), Bagnato A, Colombo N, Savarese A, Scambia G, Sehouli J, Wimberger
P, Sorio R, Harter P, Mari E, McIntosh S, Nathan F, Pemberton K, Baumann K.
Affiliation(s): Author information:
(1)Regina Elena National Cancer Institute, Rome, Italy. cognetti@ifo.it
Publication date & source: 2013, Gynecol Oncol. , 130(1):31-7
BACKGROUND: In platinum-sensitive relapsed ovarian cancer, paclitaxel plus
carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral,
specific ETA-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 175 mg/m(2) iv followed by
carboplatin iv (AUC 5) on day 1 of every 3-week cycle 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 10.0 months,
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 6.7 months. 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.
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