Article Text

Download PDFPDF
Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial
  1. Alexander D Murphy1,
  2. Catharine Porter2,
  3. Ann White2,
  4. Alys Irving2,
  5. Richard Adams2,
  6. Ruby Ray2,
  7. Angela Casbard2,
  8. Reem D Mahmood1,
  9. Suman Karanth1,
  10. Cong Zhou3,
  11. Julia Pugh1,
  12. Chelsey Wheeler1,
  13. Victoria Roberts1,
  14. Giorgio Arnetoli1,
  15. Zena Salih1,
  16. Jurjees Hasan1,
  17. Claire Mitchell1,
  18. Robert D Morgan1,4,
  19. Andrew R Clamp1,4 and
  20. Gordon C Jayson1,4
    1. 1Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
    2. 2Centre for Trials Research, Cardiff University, Cardiff, UK
    3. 3National Biomarker Centre, CRUK Manchester Institute, Manchester, UK
    4. 4Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
    1. Correspondence to Professor Gordon C Jayson, Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; gordonjayson{at}nhs.net

    Abstract

    Objective Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction.

    Methods A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3–5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival.

    Results Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3–5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85–100%; n=29) and for cediranib 88% (IQR 76–93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4–11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1–20.4 months; n=17). Median follow-up was 12.4 months (8.9–not reached; n=17).

    Conclusions The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated.

    Trial registration number EudraCT 2016-004618-93

    • Ovarian Cancer

    Data availability statement

    Data are available upon reasonable request.

    Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Data availability statement

    Data are available upon reasonable request.

    View Full Text

    Footnotes

    • Presented at The data in this manuscript were presented at the 2022 European Congress of Gynaecological Oncology.

    • Contributors GCJ, CZ, and ARC designed the study. AW, AI, and RR were responsible for project management. AI, AW, AM, RDM, SK, JP, CW, VR, GA, ZS, JH, CM, RDM, ARC, and GCJ collected data. CP and AC analyzed the data. CZ analyzed post hoc data. CP, AM, AC, CZ, RDM, ARC, and GCJ interpreted the data, and wrote the manuscript. CP and AC had access to the raw data.

    • Funding The trial was sponsored by the University of Manchester and coordinated by Cardiff University Centre for Trials Research. The trial was funded by Astrazeneca, who also provided the investigational medicinal products (cediranib and olaparib). Astrazeneca had no role in designing the study, data collection, data analysis, interpretation of the results, writing of the statistical analysis final report, or the final decision to submit the manuscript.

    • Competing interests ARC and GCJ have received research funding for this and other investigator initiated studies from AstraZeneca. RDM is supported by a National Institute for Health Research Clinical Lectureship (CL-2022-06-002).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.