Colorectal Adenocarcinoma Metastatic in the Liver

This study will evaluate the safety and effectiveness of the combination of pembrolizumab and odetiglucan in patients with metastatic colorectal cancer that is predominantly in the liver.

This is a single-center, open-label, exploratory phase II trial to evaluate efficacy and safety of Retlirafusp alfa (PD-L1/TGF-βRII bispecific fusion protein) combined with standard first-line targeted-chemotherapy as conversion therapy in adult patients with initially unresectable microsatellite-stable (MSS/pMMR) colorectal adenocarcinoma liver metastases. Two pre-defined cohorts are enrolled: Cohort 1 for RAS/BRAF wild-type left-sided primary tumor (mFOLFOX6 + cetuximab + Retlirafusp alfa); Cohort 2 for RAS/BRAF-mutant or right-sided primary tumor (CAPEOX + bevacizumab + Retlirafusp alfa).

The goal of this clinical trial is to assess how many patients with initially inoperable colorectal liver metastasis are able to have a liver surgery after treatment with hepatic artery infusion chemotherapy and standard of care systemic chemotherapy.

This study aims to develop a highly sensitive, specific, and cost-effective blood assay for early detection of colorectal adenomas and cancer, using advanced machine learning and state-of-the-art biological analyses.

At the time of diagnosis, 25% of patients with colorectal cancer present with liver metastasis (CRLM). Among patients with localized colorectal cancer (Stages I-III), 50% to 70% will develop liver metastases during the course of their disease. Surgery in combination with intravenous (IV) chemotherapy represents the only chance of cure for selected patients by removing all liver metastases and treat residual microscopic disease by postoperative chemotherapy for 3 months. However, up to two-thirds of patients will experience a relapse, with about two-thirds of recurrences occurring in the liver. Hepatic arterial infusion (HAI) chemotherapy has been proposed to improve the efficacy of chemotherapy by increasing the concentration of the drug in the liver. This treatment is currently administered by infusion through a specific catheter placed in the artery feeding the liver parenchyma, connected to a subcutaneous port-a-cath system. Several trials have shown that the administration of floxuridine or oxaliplatin via HAI combined with IV chemotherapy achieves a higher response rate compared to IV chemotherapy alone in patients with unresectable colorectal liver metastases. HAI chemotherapy has thus become an attractive therapeutic option for patients who underwent curative-intent surgery to reduce the risk of hepatic recurrence. The investigators recently demonstrated in the PACHA-01 phase II randomized study a 47% decrease of hepatic recurrence risk by HAI of oxaliplatin compared to IV chemotherapy alone, despite a higher but manageable toxicity among 99 patients who underwent curative surgery considered at high risk of recurrence. Moreover, this study showed promising results in terms of time to recurrence and survival. Moreover, feasibility has improved in recent years with the development of non-invasive techniques for HAI. The investigators propose to conduct the PACHA-02 trial to evaluate the efficacy in terms of disease-free survival of oxaliplatin administered via HAI in combination with IV chemotherapy after curative resection in patients with colorectal cancer at high risk of recurrence. A total of 272 patients who will undergo curative surgery for at least 4 CRLM with no residual disease on imaging performed within 4 weeks after surgery will be included. Patients will then be randomized to receive oxaliplatin-based chemotherapy either via HAI or IV combined with standard IV chemotherapy, every 2 weeks for at least 3 months. The primary objective of this study will be to determine if the administration of oxaliplatin via HAI increases the time between treatment and disease recurrence compared to IV administration. The secondary objectives include overall survival, hepatic recurrence-free survival, safety, pattern of recurrence, and quality of life.

Procedural data will be recorded from patients with liver metastases from colorectal cancer who have received at least one course of systemic chemotherapy and who have been assessed by an appropriately constituted MDT (or equivalent) as appropriate to receive irreversible electroporation.