Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial

摘要: Summary Background Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which poor prognostic factor in colorectal cancer. This study aimed to test napabucasin advanced Methods was double-blind randomised phase 3 trial done at 68 centres Canada, Australia, New Zealand, and Japan. Patients with good Eastern Cooperative Oncology Group (ECOG) performance status (0–1) for whom all available standard therapies had failed were eligible the study. randomly assigned (1:1) receive placebo or through web-based system permuted block method, after stratification by ECOG status, KRAS previous VEGF treatment, time from diagnosis of metastatic disease. 480 mg matching taken orally every 12 h. All patients received best supportive care. The primary endpoint overall survival assessed an intention-to-treat analysis. final analysis this trial, registered ClinicalTrials.gov, number NCT01830621. Findings Accrual began on April 15, 2013, stopped futility May 23, 2014, point 282 undergone randomisation (138 group 144 group). Overall did not differ significantly between groups: median 4·4 months (95% CI 3·7–4·9) 4·8 (4·0–5·3) (adjusted hazard ratio [HR] 1·13, 95% 0·88–1·46, p=0·34). safety population included 136 group. More who any grade treatment-related diarrhoea (108 [79%] patients), nausea (69 [51%]), anorexia (52 [38%]) than (28 [19%] patients, 35 [24%], 23 [16%], respectively). most common severe (grade worse) adverse events abdominal pain (five [4%] receiving vs five [3%] placebo), (21 [15%] one [1%]), fatigue (14 [10%] eight [6%]), dehydration (six [1%]). 251 (89%) data pSTAT3 expression, 55 (22%) pSTAT3-positive tumours (29 group, 26 In prespecified biomarker longer (median 5·1 [95% 4·0–7·5] 3·0 [1·7–4·1]; HR 0·41, 0·23–0·73, p=0·0025). Interpretation Although there no difference groups unselected population, STAT3 might be important target treatment elevated expression. Nevertheless, these results require validation. Funding Canadian Cancer Society Research Institute Boston Biomedical.