Iveson 2014.

Methods	International RCT (43 centers), Phase II
Participants	Number of participants: 121 (February 2009 to November 2010) Number randomized: Experimental group A (ECX (epirubicin, cisplatin, and capecitabine) + rilotumumab 7.5 mg/kg): 42 Experimental group B (ECX + rilotumumab 15 mg/kg): 40 Control group (ECX + placebo): 39 Number evaluated: Experimental group A: 42, age (median and range): 62 (27 ‐ 78) years Experimental group B(ECX + rilotumumab 15 mg/kg): 40, age (median and range): 59.5 (28 ‐ 76) years Control group: 39, age (median and range): 60 (39 ‐ 79) years Diagnosis: patients with unresectable locally‐advanced or metastatic gastric or esophagogastric junction adenocarcinoma Inclusion: eligible patients should: be > 18 years; have pathologically‐confirmed, unresectable locally‐advanced or metastatic gastric or esophagogastric junction adenocarcinoma (tumors of the distal esophagus within 5 cm of the esophagogastric junction were allowed); measurable and non‐measurable disease; ECOG performance status of 0 or 1; life expectancy of at least 3 months; adequate organ function; hemoglobin concentration of at least 90 g/L; absolute neutrophil count of at least 1.5*10⁹ cells per L; platelet count of at least 100*10⁹ platelets per L (without transfusion < 14 days before enrolment or randomization); creatinine clearance of at least 60 mL/min (calculated or measured); AST and ALT concentrations of ≤ 2·5 × ULN, or AST and ALT of 5 × ULN or less in the presence of liver metastasis; total bilirubin 1·5 × ULN or less; and partial thromboplastin time 1·5 × ULN or less and international normalization ratio ≤ the ULN
Interventions	Experimental group A : intravenous infusion of rilotumumab 7.5 mg/kg before administration of ECX + ECX (epirubicin 50 mg/m² administered intravenously on day 1 every 3 weeks; cisplatin 60 mg/m² administered intravenously on day 1 every 3 weeks, and capecitabine 625 mg/m² taken twice a day orally on days 1 – 21 every 3 weeks) Experimental group B : intravenous infusion of rilotumumab 15 mg/kg before administration of ECX + ECX (epirubicin 50 mg/m² administered intravenously on day 1 every 3 weeks; cisplatin 60 mg/m² administered intravenously on day 1 every 3 weeks, and capecitabine 625 mg/m² taken twice a day orally on days 1 – 21 every 3 weeks) Control group: intravenous infusion of placebo before administration of ECX + ECX (epirubicin 50 mg/m² administered intravenously on day 1 every 3 weeks; cisplatin 60 mg/m² administered intravenously on day 1 every 3 weeks, and capecitabine 625 mg/m² taken twice a day orally on days 1 – 21 every 3 weeks) Treatment continued for up to 10 cycles or until disease progression, unacceptable toxicity, or withdrawal of informed consent
Outcomes	Duration of follow‐up (median): 21.7 months (IQR 20.5 ‐ 23.5) PFS, OS, overall response, adverse events
Notes	Sponsor: Amgen The sponsor was involved in the study design, data collection, data analysis, results interpretation, and manuscript preparation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The randomisation list was generated using permuted blocks with a block size of six and prepared by an individual independent of the study team"
Allocation concealment (selection bias)	Low risk	"Treatment allocation was assigned using an interactive voice response system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Patients, investigators, and the study team were masked to treatment allocation, which was straightforward because rilotumumab is a colourless liquid."
Blinding of outcome assessment (detection bias) OS, Serious adverse events	Low risk	These outcomes were unlikely to be affected by the blindness status of assessors
Blinding of outcome assessment (detection bias) PFS, Response, quality of life & adverse events	Low risk	"Patients, investigators, and the study team were masked to treatment allocation, which was straightforward because rilotumumab is a colourless liquid."
Incomplete outcome data (attrition bias) All outcomes	Low risk	121 randomized participants were included in analysis (100%)
Selective reporting (reporting bias)	Low risk	Prior protocol was available
Other bias	Low risk	No obvious potential source of bias