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Abstract
Introduction/Background Systemic treatment of platinum-resistant advanced ovarian cancers (PROC) utilises cytotoxic chemotherapy and vascular endothelial growth factor receptor (VEGFR) inhibitors. However, patients at risk for malignant bowel obstruction (MBO) are excluded from this efficacious combination due to risk of bowel perforation.
Methodology We conducted a Simon’s two-stage trial combining oral VEGFR inhibitor cediranib (20 mg/day) with weekly paclitaxel (70 mg/m2), in participants with recurrent PROC and clinical and/or radiological features indicating an increased risk of developing MBO. Primary endpoint was number of patients free of grade 3–5 gastrointestinal perforation (GIP) or fistula, from those who received ≥5 days and ≤18 weeks cediranib, causally related to cediranib. With 90% power and 5% significance, 24 evaluable patients were required, with 22 free of GIP or fistula to demonstrate safety. Cediranib could start with chemotherapy, or at cycle 2 or 3, once bowel symptoms were CTCAE grade ≤2. Previous bevacizumab exposure and prior MBO were permitted. Patients were continued on cediranib maintenance after paclitaxel completion, and optionally proceeded to cediranib plus olaparib (300 mg bd) at disease progression.
Results 30 participants were enrolled from March 2018 to February 2021. 90% ECOG 0–1, 97% had symptoms showing risk of bowel obstruction. 1 patient died before any treatment. 12 received paclitaxel only (bowel symptoms didn’t improve or deterioration) and subsequently progressed. 17 patients were evaluable for primary endpoint; none developed GIP or fistula. Three cediranib+paclitaxel participants developed bowel obstruction (any grade; including one receiving cediranib+olaparib). Three participants had grade 3+ SAEs causally related to cediranib+/-olaparib (one diarrhoea; one diarrhoea and TIA; one vomiting). Median progression-free survival was 5.4 months (95%CI: 4.18–8.25), and overall survival 15.2 months (95%CI: 8.52–20.5).
Conclusion There is no evidence that combining cediranib and taxane chemotherapy is associated with serious toxicity or of developing GIP/fistula, although this is underpowered due to participant withdrawal.