Study protocol for a single-arm phase Ib/II trial of Ivonescimab combined with adapted guided stereotactic body radiotherapy and chemotherapy in patients with locally advanced pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective treatment options, contributing to its high mortality of rate. Radiotherapy has shown effect in converting PDAC from a "cold tumor" to "hot tumor”, thus enhancing its response to immunotherapy. The synergistic effect of radiotherapy and immunotherapy may further improve therapeutic efficacy. Additionally, studies have demonstrated that vascular endothelial growth factor (VEGF) inhibitors can enhance the effectiveness of anti-programmed cell death 1/ligand 1 (anti-PD-1/PD-L1) antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immune-permissive TME. This study aims to investigate the efficacy and safety of Ivonescimab-a bispecific antibody against programmed cell death protein 1 and VEGF-in combined with stereotactic body radiotherapy (SBRT) and chemotherapy for treating locally advanced pancreatic cancer (LAPC). This is a single-arm, Phase Ib/II clinical study designed to recruit 37 patients with LAPC (NCT06844422). Before enrollment, participants must undergo a comprehensive clinical evaluation, including imaging and cytological or histopathological examinations. The objective of Phase Ib was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended Phase II dose (RP2D) of Ivonescimab. The Phase Ib component follows a dose-escalation design using a 3 + 3 methodology to deterime DLT over 4-week period, establishing the recommended Phase II dose (RP2D) of Ivonescimab. In Phase II, the study aimed to investigate the median progression-free survival (mPFS) for patients with PDAC. The Phase II portion is a single-arm study utilizing the RP2D of Ivonescimab as determined in Phase Ib. Initially, participants will receive Ivonescimab in combination with SBRT (25-50 Gy/5F) over 2 weeks, followed by up to 8–10 cycles of Ivonescimab combined with modified FOLFIRINOX (mFOLFIRINOX; oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2 and fluorouracil 2400 mg/m2). Maintenance treatment with Ivonescimab may continue based on individual tolerance, up to 12 months or until intolerable toxicity or disease progression. This trial is to assess the safety and efficacy of Ivonescimab in combination with SBRT and chemotherapy as first-line treatment for LAPC. The fingdings from this Phase Ib/II study will provide critical insights to inform future treatment selection and therapeutic planning for patients with LAPC.