Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial

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Background

Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1–3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer.

Methods

In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase.....

Research in context

Evidence before this study

In 2003, we published the results of the International Collaborative for Ovarian Neoplasia (ICON) 4 trial in The Lancet, showing the value of platinum-combination treatment for women relapsing more than 6 months after completing first-line treatment for ovarian cancer. This set a new standard of care with an improvement in overall survival, but the benefit was slight. In around 2006, unpublished data began to emerge showing that inhibitors of angiogenesis, blocking either the vascular endothelial growth factor (VEGF) ligand or its receptor could lead to shrinkage of ovarian tumours and delayed disease progression. We designed a three-arm, placebo-controlled, randomised trial (ICON6) in collaboration with the Gynaecological Cancer InterGroup adding the VEGF receptor tyrosine kinase inhibitor cediranib to chemotherapy and then continued as maintenance treatment. No previous trials of maintenance treatment with a molecularly targeted treatment in ovarian cancer had been done, although during this time, trials with the monoclonal antibody bevacizumab were in development for first-line treatment and for women with first relapse......

Refers To

• John Norrie

• ICON-6: the danger of changing study design midstreamThe Lancet, Volume 387, Issue 10023, 12–18 March 2016, Pages 1031-1032 

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• • ......These design changes should not have been necessary, and clinical trials should be better structured to make sure this does not recur.

    The original study design promised more reliable evidence, but instead of randomly assigning roughly 2000 participants, the study underwent a major revision with just 387 participants randomly assigned because the drug company involved (AstraZeneca) decided (on Sept 14, 2011) to cease commercial development of cediranib, owing to negative findings for overall survival in three pivotal phase 3 studies on different cancers.^{3, 4 and 5} With insufficient remaining drug stock and its short shelf life, as well as AstraZeneca being unwilling to manufacture additional supplies, a fundamental redesign (or complete abandonment) became necessary.......