Safety and Efficacy of CAPOX Combined with Bevacizumab plus Pembrolizumab as Neoadjuvant Treatment of pMMR/MSS Type Locally Advanced Colorectal Cancer Patients: Study Protocol for a Single-arm, Phase Ib, Prospective Trial (COBP)

Abstract

Abstract Background: Different from microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC), almost 95% of CRC patients are microsatellite stable (MSS) which have been referred to as “cold” tumors showing primary resistance to immune checkpoint inhibitor (ICI). Pre-clinical research has elucidated the synergistic effect of ICI and anti-vascular therapy. Normalization of tumor blood vessels can improve immunotherapy. Moreover, chemotherapy has a pro-apoptotic effect on vascular endothelium to enhance the effect of promoting normalization of tumor blood vessels which can in turn promote tumor delivery of specific T cells and chemotherapy drugs into tumor tissue. Based on this, we plan to investigate the safety and efficacy of CAPOX combined with Bevacizumab plus Pembrolizumab (COBP) as neoadjuvant treatment of mismatch repair-proficient (pMMR) or MSS type locally advanced CRC patients. Methods: This is a prospective, single-center, single-arm, phase Ib study, mainly including patients with pMMR/MSS type locally advanced CRC, to explore the safety and feasibility of pembrolizumab combined with bevacizumab and CAPOX regime. Capecitabine will be administered orally at a dose of 1000 mg/m2 twice daily from days 1 to 14, every 3 weeks. Oxaliplatin, bevacizumab, and pembrolizumab will be given intravenously at a dose of 135 mg/kg, 7.5 mg/kg, and 200 mg respectively on day 1, every 3 weeks. After 4 cycles of treatment, patients will receive CAPOX for another one cycle. After neoadjuvant therapy, radical surgery will be performed for patients operable. The primary endpoints include adverse effects, R0 resection rate, pathologic complete response rate, and tumor regression grade. The second endpoints include 1/2/3-year disease-free survival, 1/2/3-year overall survival, and quality of life. Discussion: The COBP study is a single center phase Ib study, which aims to initially explore the safety and preliminary effectiveness of COBP regime in locally advanced CRC patients. We hope that the results of this study can provide a direction for future exploration and further improve the outcome of patients. Trial registration: ClinicalTrials.gov NCT05585814. Registered on October 19, 2022.