LBA25_PR - CIRCCa: A randomised double blind phase II trial of carboplatin-paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/...

Date 28 September 2014
Event ESMO 2014
Session Gynaecological cancers
Topics Anti-Cancer Agents & Biologic Therapy
Cervical Cancer
Presenter Paul Symonds
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors P. Symonds1, C. Gourley2, S. Davidson3, C. West4, C. Dive5, J. Paul6, K. Carty7, E. McCartney6, D. Rai7, S. Banerjee8, D. Jackson9, R. Lord10, M. McCormack11, E. Hudson12, N. Reed13, M. Flubacher14, P. Jankowska15, M. Powell16
  • 1Department Of Cancer Studies And Molecular Medicine, University Hospitals of Leicester NHS Trust Leicester Royal Infirmary, LE1 5WW - Leicester/GB
  • 2Mrc Institute Of Genetics And Molecular Medicine, Edinburgh Cancer Research UK Centre, EH4 2XR - Edinburgh/GB
  • 3Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 4Institute Of Cancer Sciences, The University of Manchester, M204BX - Manchester/GB
  • 5Institute Of Cancer Sciences, Paterson Institute for cancer research University of Manchester, M20 4BX - Manchester/GB
  • 6Cruk Clinical Trials Unit, Beatson Woscc, University of Glasgow, G12 0YN - Glasgow/GB
  • 7Beatson West Of Scotland Cancer Centre, CRUK Clinical Trials Unit, G12OYN - Glasgow/GB
  • 8Department Of Medicine, Royal Marsden HospitalNHS Foundation Trust, GB-SW3 6JJ - London/GB
  • 9Institute Of Oncology, Leeds Cancer Centre, St James's University Hospital, LS9 7TF - Leeds/GB
  • 10Clatterbridge Centre For Oncology, University of Liverpool, CH63 4JY - Liverpool/GB
  • 11Oncology Department, 1st Floor Central, University College Hospital, NW1 2PG - London/GB
  • 12Oncology, Velindre Hospital, Cardiff/GB
  • 13Beatson West Of Scotland Cancer Centre, Gartnavel General Hospital, G12 0YN - Glasgow/GB
  • 14Oncology Department, Poole Hospital, BH152JB - Dorset/GB
  • 15Musgrove Park Hospital, Taunton & Somerset NHS Foundation Trust, TA1 5DA - Somerset/GB
  • 16St Bartholomew's Hospital, Barts and The London NHS Trust, EC1A 7BE - London/GB

Abstract

Aim

Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly (response rates 20-30%) to conventional chemotherapy with an overall survival of less than a year. High tumour angiogenesis along with high levels of intratumoural vascular endothelial growth factor (VEGF) are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGF receptors1,2&3.

Methods

Patients were randomised (1:1) to receive carboplatin AUC5 + paclitaxel 175mg/m2 3 weekly for a maximum of 6 cycles plus 20mg cediranib daily (arm A) or placebo (arm P) until disease progression. Plasma VEGFR-2 levels were measured at baseline and at 28 days into chemotherapy. The primary end-point was progression- free survival (PFS). Secondary end-points included changes in sVEGFR-2 from baseline to day 28, overall survival (OS), response, toxicity and quality of life. The study has approximately 80% power (20% 1-sided) to detect a 60% increase in median PFS from 4 to 6.4 months.

Results

69 patients were randomised (35 P; 34 A) during 2010-12, 13% with local relapse only, 30% with extra pelvic metastases and 57% with both. 83% had 1 line of previous treatment. 79% completed 6 cycles of chemotherapy. 22% stopped P and 17% stopped A for treatment related reasons. Median PFS (wks; 80% CI) is 30 (29, 31) on P versus 35 (32, 38) on A (hazard ratio A/P [HR] 0.61; 80% CI: (0.41, 0.89); P = 0.046). Median change in log10 sVEGFR-2 from baseline was .067 (n = 22) on P compared to -.036 (n = 18) on A (P < .001). Median OS was 63 wks (55, 80) for P versus 59 (50, 75) for A (HR: 0.93; 80% CI: 0.64, 1.36; P = 0.401). Overall response rate (CR/PR) was 42% for P and 66% for A (P = .030). On A more patients experienced grade 2/3/4 diarrhoea (50% v 18%, p = .005) and hypertension (34% v 12%, p = .038). During the drug only period 9% of P patients experienced grade 2/3/4 toxicity compared to 19% on A.

Conclusions

PFS, inhibition of VEGFR-2 receptor and response rate were all significantly increased on arm A. This was accompanied by a manageable toxicity increase (diarrhoea and hypertension). Acknowledgements: This research was supported by CRUK,ECMC funding and conducted with support from Investigator-Sponsored Study Collaboration between AstraZeneca and the NCRN. Study Sponsors: NHS Greater Glasgow & Clyde and University of Glasgow.

Disclosure

C. Gourley: Personal (advisory board membership) and non-personal specific and non-specific interests in AstraZeneca, GlaxoSmithKline and Roche; S. Banerjee: Conflict of Interest - AstraZeneca (not directly financially remunerated); R. Lord: Has acted on advisory boards for AstraZeneca but not in relation to Cediranib. All other authors have declared no conflicts of interest.