Background: LSTA1, formerly known as CEND-1, is a novel cyclic peptide which selectively binds to αv/β3 and β5 integrins, which are upregulated in solid tumors, where it undergoes protease cleavage producing a C-end rule peptide fragment (CendR) that selectively binds to and activates neuropilin-1 (NRP1). Once CendR binds NRP1, the CendR pathway is activated, leading to increased vascular permeability of tumors resulting in increased drug delivery and tumor accumulation of co-administered chemotherapeutic agents. Here we report the safety and efficacy results from a Phase Ib/II, multicenter study of LSTA1 plus (SoC) gemcitabine and locally produced nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: The study included a 7-day safety run-in and dose expansion/extension parts. Previously untreated patients with histologically confirmed mPDAC and ≥1 target lesion were treated with systemic chemotherapy and received LSTA1 (1.6 mg/kg or 3.2 mg/kg), gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m²) on days 1, 8, 15, of each 28-day treatment cycle. LSTA1 alone was given during run-in to observe PK/PD. Treatment continued until disease progression or other discontinuation events. The primary endpoints were safety and preliminary efficacy. Results: As of 30 Nov 2022, 38 patients were enrolled at 10 sites in China (12 at 1.6 mg/kg; 26 at 3.2mg/kg). The median follow-up time was 6.28 months. 37 (97.4%) patients experienced TEAEs and 31 (81.6%) patients experienced grade≥3 TEAEs. The most common TEAEs were hematologic toxicity related to chemotherapy. The ORR was 42.9% (15/35) and DCR was 82.9% (29/35). The ORR in 1.6 mg/kg and 3.2 mg/kg groups was 45.5% and 41.7%, respectively. The mPFS in 1.6 mg/kg and 3.2 mg/kg groups was 7.43 months (95% CI: 0.59-NE) and 5.75 months (95% CI: 3.25-7.46) respectively. mOS was not reached. NRP1 expression levels were tested at baseline; six of whom had expression ≥40%. Of those, 4 had PRs and 2 had SD (ORR=66.7%; DCR=100%). The mPFS was 7.5 months. Conclusions: LSTA1 combined with SoC showed an acceptable safety profile in patients with mPDAC. Compared with historical SoC data, LSTA1 plus SoC numerically improved ORR and PFS. Higher NRP1 expression is associated with better ORR and PFS, suggesting NRP1 may be a potential biomarker of LSTA1 plus chemotherapy for mPDAC treatment. Further study is ongoing. Clinical trial information: NCT05052567.