NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121).

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).

Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. METHODS: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. FINDINGS: 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. INTERPRETATION: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. FUNDING: ImClone Systems.

Oxaliplatin/5-fluorouracil-based adjuvant chemotherapy as a standard of care for colon cancer in clinical practice: Outcomes of the ACCElox registry.

AIM: The ACCElox registry was set up to assess therapeutic management of early-stage colon cancer with oxaliplatin/5-fluorouracil (5-FU)-based regimen and the duration of adjuvant chemotherapy in current clinical practice. METHODS: This prospective observational study was conducted between 2006 and 2008 in 19 countries on 1548 newly diagnosed patients with stage II/III colon cancer, who had complete resection of the primary tumor and treated with at least one dose of oxaliplatin. The patient/disease characteristics, dose intensity, toxicity management, treatment delay and duration of disease-free survival (DFS)/relapse were assessed. RESULTS: About 73 and 27% of the patients were diagnosed with stage III (Dukes C) and stage II (Dukes B2) colon cancer, respectively. Overall, 74.4% patients completed the prescribed chemotherapy (FOLFOX 88%) and 97.6% patients received at least two cycles of oxaliplatin chemotherapy. The median actual dose intensity of oxaliplatin per cycle was 85 mg/m(2) . Relapse within 3 years occurred in 18.4% of patients with similar rate in all three groups (FOLFOX - 18.1%, FLOX - 19%, XELOX - 18.6%). At 3 years follow-up only 72 deaths were reported. The most common adverse events (AEs) at any cycle were neutropenia (63.9%), thrombocytopenia (23.3%), diarrhea (9.7%), sensory neuropathy (4.5%) and infection (2.6%). Disorders of central and peripheral nervous systems were frequently reported AEs at 6 months (54.3%, grade ≥1) and 12 months (36.4%, grade ≥1) of follow-up. CONCLUSION: Majority of the patients completed the prescribed oxaliplatin/5-FU regimen. There was no significant difference in the DFS among these regimens. Our results confirm the favorable benefit/risk profile of oxaliplatin/5-FU-based regimens in this setting in clinical practice.