Past clinical trials in ovarian cancer

Through analysis of thousands of patients in clinical trials around the world, we have developed new ways of detecting and monitoring ovarian cancer based on changes in levels of CA125 – a chemical present in the blood of patients with ovarian cancer. These tests also provide an early indication of patients’ responses to different treatments. Our definitions, based on changes in CA125 levels (previously known as the “Rustin” criteria), have now been accepted by all major trial groups around the world and are called the Gynecological Cancer Inter-Group (GCIG) criteria. The CTRT helped fund the CA125 doubling trial that demonstrated that CA125 changes could be used to assess new drugs which are relatively non-toxic and work by controlling rather than killing cancers (Hall et al., 2014).

Another major area of development that has been supported by CTRT and undertaken at Mount Vernon Cancer Centre over the last 20 years, involves a group of drugs that attack the blood vessels which prevents ovarian cancer from growing. The CTRT has contributed to the necessary research teams that allow our patients access the clinical trials with the anti-angiogenic agents (ICON 7, ICON6, AMG386). These agents have shown prolong remissions in patients with persistent and relapsed ovarian cancer (Hall, 2019; Oza, 2015; Perren, 2011). Professor Hall was the chief investigator that headed the national ‘METRO-BIBF’ clinical trial. She explored another anti-angiogenic called nintedanib, with oral cyclophosphamide (Hall et al., 2020). Although the addition of nintedanib did not lengthen the time in remission for patients in this study, it was useful in highlighting the value of oral cyclophosphamide in this patient group. The repurposing of older drugs such as cyclophosphamide is becoming increasingly valuable. At CTRT we hope that future clinical trials can help us explore the combination of cyclophosphamide with alternative agents, which may induce longer and successful remissions for these patients.

The second group of drugs to target the blood vessels are vascular disruptive agents (VDAs). Professor Rustin was an instrumental figure in the early development of two of these drugs, combretastatin and fozbretabulin. He was the Chief Investigator of the PAZ-FOZ trial in patients with recurrent ovarian cancer, this investigated combining a vascular disruptive agent (fozbretabulin) with an anti-angiogenic (Pazopanib) – the drugs that attack tumour blood vessels in very different ways (see figure 1). Sadly, the combination caused too many cardiac problems for widespread development, although the principle of this combination was very successful (Morgan et al., 2020).

Figure 1

Figure 2

Comparison of the action of antiangiogenic and vascular disruptive agents.

There was an article in the Daily Mail (14 October 2014) regarding this trial – Is this the Ovarian Cancer Breakthrough Women have Prayed For?

In the laboratory

CTRT funds the tuition and bench fees for a clinical research fellow who is in collaboration with Dr Emmanouil Karteris.

Dr Emmanouil Karteris is a Senior Lecturer at Brunel University (Laboratory of Cancer Biomarkers and Cellular Endocrinology) and is exploring the circulating cancer-associated cells within patients that have ovarian and uterine cancer. Her PhD thesis also integrates CT scans imagery that shows the changes in some ovarian cancer patients with molecular findings from their blood samples. For us to predict which therapies might be most effective is dependent on the ability to identify novel imaging markers from the molecular findings.

PhD students, clinical research fellow and scientific officer with laboratory head Dr Emmanouil Karteris and Professor Marcia Hall (centre)

Bibliography

Carter, T., Jeyaneethi, J., Kumar, J., Karteris, E., Glynne-Jones, R. and Hall, M., 2020. Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients. Cancers, 12(8), p.2229. DOI: 10.3390/cancers12082229

Chudasama, D., Bo, V., Hall, M., Anikin, V., Jeyaneethi, J., Gregory, J., Pados, G., Tucker, A., Harvey, A., Pink, R. and Karteris, E., 2017. Identification of cancer biomarkers of prognostic value using specific gene regulatory networks (GRN): a novel role of RAD51AP1 for ovarian and lung cancers. Carcinogenesis, 39(3), pp.407-417. DOI: 10.1093/carcin/bgx122

Hall, M., Petruckevitch, A., Pascoe, J., Persic, M., Tahir, S., Morgan, J., Gourley, C., Stuart, N., Crawford, S., Kornbrot, D., Qian, W. and Rustin, G., 2014. Using Serum CA125 to Assess the Activity of Potential Cytostatic Agents in Ovarian Cancer. International Journal of Gynecologic Cancer, 24(4), pp.676-681. DOI: 10.1097/igc.0000000000000116

Hall, M., Bertelli, G., Li, L., Green, C., Chan, S., Yeoh, C., Hasan, J., Jones, R., Ograbek, A. and Perren, T., 2019. Role of front-line bevacizumab in advanced ovarian cancer: the OSCAR study. International Journal of Gynecologic Cancer, 30(2), pp.213-220. DOI: 10.1136/ijgc-2019-000512

Hall, M., Dehbi, H., Banerjee, S., Lord, R., Clamp, A., Ledermann, J., Nicum, S., Lilleywhite, R., Bowen, R., Michael, A., Feeney, A., Glasspool, R., Hackshaw, A. and Rustin, G., 2020. A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer. Gynecologic Oncology, 159(3), pp.692-698. DOI: 10.1016/j.ygyno.2020.09.048.

Kumar, J., Chudasama, D., Roberts, C., Kubista, M., Sjöback, R., Chatterjee, J., Anikin, V., Karteris, E. and Hall, M., 2019. Detection of Abundant Non-Haematopoietic Circulating Cancer-Related Cells in Patients with Advanced Epithelial Ovarian Cancer. Cells, 8(7), p.732. DOI:10.3390/cells8070732

Morgan, R., Banerjee, S., Hall, M., Clamp, A., Zhou, C., Hasan, J., Orbegoso, C., Taylor, S., Tugwood, J., Lyon, A., Dive, C., Rustin, G. and Jayson, G., 2020. Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. Gynecologic Oncology, 156(3), pp.545-551. DOI: 10.1016/j.ygyno.2020.01.005

Oza, A., Cook, A., Pfisterer, J., Embleton, A., Ledermann, J., Pujade-Lauraine, E., Kristensen, G., Carey, M., Beale, P., Cervantes, A., Park-Simon, T., Rustin, G., Joly, F., Mirza, M., Plante, M., Quinn, M., Poveda, A., Jayson, G., Stark, D., Swart, A., Farrelly, L., Kaplan, R., Parmar, M. and Perren, T., 2015. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. The Lancet Oncology, 16(8), pp.928-936. DOI: 10.1016/S1470-2045(15)00086-8.

Perren, T., Swart, A., Pfisterer, J., Ledermann, J., Pujade-Lauraine, E., Kristensen, G., Carey, M., Beale, P., Cervantes, A., Kurzeder, C., Bois, A., Sehouli, J., Kimmig, R., Stähle, A., Collinson, F., Essapen, S., Gourley, C., Lortholary, A., Selle, F., Mirza, M., Leminen, A., Plante, M., Stark, D., Qian, W., Parmar, M. and Oza, A., 2011. A Phase 3 Trial of Bevacizumab in Ovarian Cancer. New England Journal of Medicine, 365(26), pp.2484-2496. DOI: 10.1056/NEJMoa1103799

Saravi, S., Katsuta, E., Jeyaneethi, J., Amin, H., Kaspar, M., Takabe, K., Pados, G., Drenos, F., Hall, M. and Karteris, E., 2020. H2A Histone Family Member X (H2AX) Is Upregulated in Ovarian Cancer and Demonstrates Utility as a Prognostic Biomarker in Terms of Overall Survival. Journal of Clinical Medicine, 9(9), p.2844. DOI: 10.3390/jcm9092844