Does Cediranib Prevent Bowel Perforation in Platinum-resistant Ovarian Cancer

Ovarian cancer is the fourth most common cause of female cancer death and the commonest cause of gynaecological cancer death, accounting for 4,000 lives a year in the UK and 22,000 in the United States (1,2). The most common cause of death is malignant bowel obstruction, which occurs because of tumour physically and neurologically arresting bowel function (3).

New treatment strategies are required to address malignant bowel obstruction, which usually occurs in patients whose disease has become resistant to platinum-based chemotherapy. Several studies have reported higher response rates and increased PFS when a VEGF pathway inhibitor is combined with cytotoxic therapy in the first line (4,5), platinum-sensitive (6,7) and platinum-resistant recurrent disease settings (8). In the AURELIA study, the addition of the anti-angiogenic, monoclonal anti-VEGF antibody, bevacizumab, to physician's choice of cytotoxic agent significantly improved PFS. However, this study excluded patients who had received more than three previous regimens of treatment and those with clinical or radiological features of bowel obstruction on the basis that previous data had shown that the administration of bevacizumab to patients with prior bowel surgery, pelvic disease involving the recto sigmoid or symptoms of bowel obstruction would significantly increase the risk of bowel perforation(9), which can be fatal.

The above data demonstrate that there is an unmet need for a VEGF inhibitor that can be safely combined with cytotoxic therapy, which would increase the response rate and PFS in this population. The MITO-11 study demonstrated the safety and potential efficacy of the combination of pazopanib with weekly paclitaxel in platinum resistant disease (11) and the investigators have demonstrated in the in-house trial of cediranib with radiotherapy in colorectal cancer (DREAM trial; manuscript in preparation) that cediranib is effective and safe in the context of significant bowel wall disease, where bevacizumab has been previously reported to induce significant toxicity (12,13).

Taking these findings together, there is a strong rationale to develop a safe VEGF inhibitor-combination regimen in the setting of patients at risk of subacute bowel obstruction from ovarian cancer. Here, the investigators will evaluate the safety and efficacy of the potent VEGF receptor tyrosine kinase inhibitors (RTKi), cediranib, with weekly paclitaxel/nab-paclitaxel in women who are at risk of developing malignant bowel obstruction from ovarian cancer; a population in which bevacizumab is contra-indicated. Any risk to the patient's bowel will be minimized by bringing the abdominal disease under control with weekly paclitaxel /nab-paclitaxel for 1-3 cycles (3-9 weeks) before introducing the combination of paclitaxel/nab-paclitaxel with cediranib.

There is a critical need to develop effective and safe treatment regimens for patients with subacute bowel obstruction from ovarian cancer. Several trials have demonstrated the clinical benefit of adding bevacizumab to cytotoxic therapy in various settings in the disease yet in sub-acute bowel obstruction or in moderately heavily pre-treated patients, the antibody is contra-indicated due to the risk of bowel perforation or fistula.

Several findings suggest that VEGF RTKi are safer than antibodies in the presence of bowel dysfunction while preserving the efficacy advantage of the combination regimen. Here, we will evaluate the safety of the potent VEGF RTKi, cediranib, in combination with weekly paclitaxel in a cohort of patients at risk of developing malignant bowel obstruction, for whom bevacizumab is contraindicated.

Paclitaxel will be administered in CEBOC at 80mg/m2/week on days 1, 8 and 15 of a 3 week schedule, where the plan will be for patients to receive 6 cycles of treatment. The treatment is being given on a continuous weekly schedule in the same way that paclitaxel was prescribed in two large randomised trials of paclitaxel with a VEGF inhibitor. In one trial the VEGF inhibitor was the monoclonal anti-VEGF antibody, bevacizumab (14) and in the other, the VEGF receptor tyrosine kinase inhibitor, pazopanib was used (15). These two trials demonstrated that weekly paclitaxel can be safely and effectively combined with a VEGF inhibitor. However, the pazopanib trial, which involved administration of a VEGF inhibitor of the same class as cediranib, reported that 30% of patients incurred grade 3 or 4 neutropenia yet the investigators had restricted entry to the study to patients who had only received up to 3 previous lines of treatment. In CEBOC, patients can have received any number of previous lines of treatment and therefore to mitigate the risk of neutropenia, the trial involves the prescription of paclitaxel (16) at 70mg/m2/week rather than the slightly higher dose used in these two trials. As there is no evidence of a dose-response effect beyond standard doses of paclitaxel, the proposed regimen of 70mg/m2/week remains a standard of care.

The dose of cediranib selected for CEBOC is 20mg/day, which was biologically and clinically active in early phase clinical trials (17). Early attempts to combine cediranib with cytotoxic chemotherapy using a dose of the former at 30mg/day proved intolerable and therefore the standard combination dose of cediranib in recurrent ovarian cancer was 20mg/day.

Once patients in CEBOC have completed a maximum of 18 weeks of treatment with paclitaxel, those who have stable disease or better can continue taking cediranib alone at 20mg/day; again a dose that was used as maintenance therapy in ICON6 (18). At the point of developing progressive disease in CEBOC patients will need to fulfil another set of eligibility criteria but if they remain eligible, they can then supplement the cediranib with olaparib. The reason that the cediranib dose will remain 20mg/day in this component of CEBOC is because the phase II trial that described the activity of the combination (19) initially involved administration of a dose of cediranib 30mg/day but this had to be reduced in 77% of patients to 20mg/day. Given the amount of previous treatment the patients will have received at this point in CEBOC it is appropriate to use the more tolerable dose of cediranib, namely 20mg/day.

In CEBOC, patients who develop progressive disease while taking cediranib and who remain eligible to continue in the trial, will be prescribed olaparib tablets 300mg bd in addition to cediranib 20mg/day. The original formulation of olaparib was as 50mg capsules and the dose of capsules was 400mg bd. As the capsules only contained 50mg olaparib, the number of capsules patients had to take was considerable. Because of this, a tablet formulation of olaparib was developed, which resulted in the same exposure to olaparib when 300mg tablets twice daily were compared with capsules at 400mg twice daily, yielding similar clinical efficacy and toxicity while reducing the pill burden to four 150mg tablets per day (20).

The recommended monotherapy tablet dose of 300mg bd has now been evaluated as maintenance therapy in BRCA-mutation associated platinum-sensitive ovarian cancer in a placebo-controlled randomised phase 3 trial (21) where it demonstrated similar efficacy to that reported for the capsule formulation in the initial seminal randomised phase II trial which resulted in EMEA approval for olaparib (7,18).

A further phase II trial confirmed that the all-tablet cediranib-olaparib combination was associated with toxicities consistent with those observed when olaparib capsules were given in combination with cediranib (22). This study established two acceptable options for phase II dosing; either cediranib 20 mg once daily and olaparib 300 mg twice daily, or cediranib 30 mg once daily and olaparib 200 mg twice daily. Based on the earlier combination study showing that a high proportion of cediranib dose reductions were required from a starting dose of 30 mg once daily (19), therefore for the purpose of this trial, participants will receive cediranib 20 mg once daily and olaparib tablets 300 mg twice daily. Intensive symptom management guidelines will also be applied within this trial.