ASCEND: a randomised, double-blinded, placebo-controlled, phase II study of gemcitabine and nab-paclitaxel with Certepetide in untreated metastatic pancreatic adenocarcinoma. An Australasian Gastro-Intestinal Trials Group (AGITG) trial

Background: The dense stroma of pancreatic ductal adenocarcinoma (PDAC) is thought to impede tumour drug delivery. Certepetide, a novel cyclic tumour-penetrating peptide internalising arginylglycylaspartic acid, promotes tumourspecific drug delivery. In the phase Ib setting, Certepetide 3.2 mg/kg with gemcitabine and nab-paclitaxel showed a 92% disease control rate at 16 weeks and was well tolerated.

Methods/design: This is a multicentre, phase II, double-blinded, placebo-controlled, randomised trial evaluating the activity and safety of Certepetide in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Initially, participants were randomised 2 : 1 to receive gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 and Certepetide 3.2 mg/kg or placebo. The trial design was updated in a protocol amendment (v4.0) to include a second placebo-controlled cohort which receives a second dose of Certepetide/placebo 4 h following chemotherapy. Treatment is administered on days 1, 8, and 15 of each 28-day cycle until progression (progressive disease). The sample size is 155 based on a clinically worthwhile increase in 6-month progression-free survival (PFS) of 16%-63% with 80% power and 95% confidence to exclude the null hypothesis. The recruitment period is 22 months and follow-up 18 months. Study endpoints are: (1) PFS; (2) objective response rate (RECIST 1.1), safety (Common Terminology Criteria for Adverse Events v5.0), overall survival, participant-reported outcomes; (3) predictive/prognostic biomarkers via archival tissue, and to assess whether a second dose of Certepetide warrants further evaluation.