131TiP - ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886

Background

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease. Standard first line chemotherapy is with gemcitabine and nab-paclitaxel, or FOLFIRINOX and median overall survival (OS) remains poor, under 12 months. The dense PDAC stroma acts as a barrier to drug delivery. CEND-1 is a novel cyclic tumor-penetrating peptide iRGD (internalizing arginylglycylaspartic acid) that may improve drug delivery by activating an endocytic/exocytic transport pathway by binding αvB3/5-integrins and downstream neuropilin-1. In the Phase 1/1b study, 29 participants with untreated metastatic PDAC were administered CEND-1 at doses of 0.2, 0.8, 1.6, and 3.2 mg/kg. No dose limiting toxicities were reported and safety was comparable to nab-paclitaxel and gemcitabine. 3.2mg/kg CEND-1 is used in ASCEND as this dose had the best objective response rate (ORR) of 61.5%.

Trial design

Multicenter Phase II double-blind placebo controlled randomized trial evaluating activity and safety of CEND-1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Endpoints: (1) PFS; (2) ORR (RECIST 1.1), safety (CTCAE v5.0), OS, patient reported outcomes (PRO; EORTC-QLQ-C30, QLQ-PAN26); (3) predictive/prognostic biomarkers via archival tissue. Sample size 125 for 2:1 randomization (CEND-1:placebo) calculated for 80% power and 95% confidence to exclude uninteresting 6 month PFS of 47% (control) in favor of 61.2% (CEND-1). Recruitment commenced on 13^th April 2022 with anticipated accrual time 18 months; 18 months follow up. 7 patients have been recruited as of 12^th July 2022. Intervention arm will receive CEND-1 (3.2mg/kg), gemcitabine (1000mg/m2), nab-paclitaxel (125mg/m2) Days 1, 8, 15 of 28 day cycle until disease progression (PD). CEND-1 replaced with placebo for control arm. Patient to complete PRO assessment at baseline then every 8 weeks until PD.

Clinical trial identification

NHMRC CTC Protocol Number: CTC0304, AGITG Protocol Number: AG0121PC, Release Date: 29 March 2022.

Legal entity responsible for the study

AGITG.

Funding

DrugCendR Australia Pty Ltd.

Disclosure

All authors have declared no conflicts of interest.