Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS: In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

Language as a barrier to cancer clinical trial accrual: assessing consenting team knowledge and practices for cancer clinical trial consent among low English fluency patients

Background: Low English fluency in large culturally diverse institutions may contribute to meager minority accrual. Our objective was to: 1) Assess knowledge of proper consenting procedures among the research team when consenting a low English fluency patient. 2) Assess the enrollment rate of participants in cancer therapeutic trials who identify a preferred language other than English. Methods: An anonymous web-based survey was distributed at a single institution to investigators, research staff and translator services to assess knowledge of consenting procedures. Patient enrollment data was retrieved from the clinical trials enrollment tracking system from January 2011 ­ October 2014 and matched to registration data indicating preferred language (N = 1521). The number and type of cancer cases from January 2011­October 2014 were retrieved from the institutional cancer registry and matched to registration data indicating preferred language. Results: Although there are many organizational in-person and web-based trainings focused on the requirements for consenting low English fluency patients, members of the research team responded correctly to only 64.8% (σ = 24.6%) of the knowledge-based portion of the survey. Of the 12,538 index cancer cases indentified, 10% preferred a language other than English. Trial enrollment rates for cancer clinical trials were similar for English (13%), Spanish (11%), and, Armenian (10%) speakers. Populations speaking Russian and Arabic had the lowest participation at 5% each. Conclusions: In order to increase enrollment into clinical trials, institutions must explore more effective training opportunities for research staff, engage interpreters and adopt recruitment and study materials in different languages (AU)