Study to Evaluate Efficacy and Safety of Selective Internal Radiation Therapy Plus Xelox, Bevacizumab and Atezolizumab (Immune Chekpoint Inhibitor) in Patients With Liver-dominant Metastatic Colorectal Cancer — SIRTCI  

Metastatic Colorectal Cancer Clinical Trial

Official title: A Prospective, Multicenter, Open-label, Phase II Study to Evaluate Efficacy and Safety of Selective Internal Radiation Therapy Plus Xelox, Bevacizumab and Atezolizumab (Immune Chekpoint Inhibitor) in Patients With Liver-dominant Metastatic Colorectal Cancer

Status Recruiting

Clinical Trial Summary

The main objective of the SIRTCI study is to evaluate the safety and efficacy of the combination chemotherapy (XELOX: Capecitabine plus oxaliplatin), anti-angiogenic (Bevacizumab), SIRT (TheraSphere®) and ICI (Atezolizumab) in patients with CRC with predominant liver metastases. SIRTCI is a single-arm, prospective, multi-centre phase II study. The main inclusion criteria are patients with MSS mRCC with predominantly non-operable liver metastases and measurable disease. Patients with extra-hepatic metastases can be included since the objective of the study is to induce local and abscopal effects of radiotherapy combined with ICI by stimulating the anti-tumour immune response to destroy both hepatic and extra-hepatic metastases.

Clinical Trial Description

About 50% of patients with CRC will develop a metastatic disease. Majority of patients have unresectable disease and unresectable liver-dominant disease represents 25% of all mCRC. Morbidity and mortality in patients with mCRC are mainly due to unresectable liver metastases. In this setting, chemotherapy (doublet or triplet) plus biological agent remains the standard of care since no prospective randomized trial demonstrates the efficacy of local treatments (chemoembolization or hepatic arterial infusion chemotherapy). Actually median PFS in patients with unresectable liver-dominant mCRC is range between 9 to 12 months and more effective treatments must be evaluated.

ICI are to date ineffective in pMMR mCRC due to low level of tumor mutational load. Nevertheless, radiation induces an immunogenic cell death able to convert a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm. In patients with liver-dominant mCRC SIRT has not shown survival improvement but only delayed disease progression in the liver. ICI improve efficacy of radiation both in irradiated lesions and non-irradiated lesions (abscopal effect). One explanation of the absence of PFS improvement with SIRT in first-line setting could be the progression of the extra-hepatic disease. Indeed, the rationale of SIRTCI 01 is to combine SIRT and ICI to induce an immune response and an abscopal effect against mCRC in order to improve control of hepatic disease (increase local SIRT efficacy with ICI) and extra-hepatic disease (increase abscopal effects of SIRT with ICI).

The aim of this study is therefore to demonstrate the synergistic anti-tumor efficacy of SIRT and ICI in patients with unresectable liver-dominant mCRC. Primary endpoint is PFS at 9 months. Main secondary endpoints are safety, response rate and OS. In addition, exploratory biomarker analyses will be performed in order to identify predictive factors of SIRT plus ICI efficacy. No safety issue was observed with XELOX/bevacizumab/atezolizumab and SIRT/FOLFOX/bevacizumab then the combination evaluated in SIRTCI 01 should be safe. Moreover oxaliplatin dose is decreased before SIRT treatment and bevacizumab is added only after SIRT treatment. All well-known predictive biomarkers of chemotherapy (mutational status, circulating tumor DNA) and ICI (tumor mutational load, immune response) efficacy will be analyzed. Additionally, pharmacokinetic analyses of Atezolizumab and centralized imaging review will be performed to evaluate morphologic and metabolic predictive markers (CT-scan, MRI, FDG PET/CT and Y90 PET/CT) of SIRT plus ICI efficacy.

This study will be the first one to use SIRT in order to induce immunogenic cell death and sensitivity to ICI. Combination of SIRT and ICI could increase immune abscopal anti-tumor effects of radiation. Indeed, once activated in one place (liver), the immune system can attack tumor lesions anywhere else in the body (lung, peritoneum…) through this abscopal effect.

SIRTCI 01 will provide informations on efficacy and safety of SIRT, ICI and chemotherapy combination in patients with unresectable liver-dominant mCRC. SIRT plus chemotherapy as well as chemotherapy plus ICI are well tolerated. TheraSphere® will be administered 3 or 4 days after cycle 2 or 3 of chemotherapy with adaptation of chemotherapy doses. Moreover, an interim analysis is planned to access efficacy of the strategy (first step after 22 evaluable patients included). At the time of the interim analysis, a complete review of the toxicities will be done to check the safety of the strategy and an independent data monitoring committee will monitor in real time all severe adverse events.

PFS at 9 months has been chosen as primary endpoint because it is a surrogate marker of OS. Actually median PFS in first-line setting with a doublet plus a biological agent is range from 8 to 11 months in unresectable mCRC and 9 to 12 months in unresectable liver-dominant mCRC, corresponding to a PFS of 50%-60% at 9 months. PFS is more reliable than response rate at 2-3 months given that the treatments used can induce tumor necrosis (SIRT) and/or initial pseudo-progression (ICI). In addition, most of patients will have a disease control/response at 2-3 months with this combination.As in all innovative phase II trials, this study should well include selected patients . A randomized phase II study with a large population does not seem appropriate in view of the limited literature on the safety and efficacy of this combination. The alternative clinical hypothesis to obtain 70% of patients alive and without progression at 9 months is ambitious and currently not achieved with current chemotherapies plus a biological agent.

The study will include patients with liver-dominant disease. Nevertheless, since the aim of the trial is to induce immune abscopal anti-tumor effects of radiation, patients with hepatic and extra-hepatic lesions will be included; extrahepatic lesions will be permitted if they are not symptomatic and if there is no organ dysfunction (up to 10 lesions). As ICI are very effective in dMMR mCRC (marketing authorization ongoing) it has been decided to exclude patients with dMMR mCRC.

The PFS obtain in SIRTCI 01 will provided a rationale for a randomized phase III study comparing chemotherapy alone (doublet or triplet ± biological agent) versus chemotherapy, SIRT and ICI combination in mCRC patients with unresectable liver-dominant disease. ;

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Immune Checkpoint Inhibitor
• Internal Radiotherapy
• Metastatic Colorectal Cancer
• MSS
• pMMR

• NCT number: NCT04659382
• Study type: Interventional
• Source: Federation Francophone de Cancerologie Digestive
• Contact: David Tougeron, MD, PhD
• Phone: 0380393404
• Email: david.tougeron@chu-poitiers.fr
• Status: Recruiting
• Phase: Phase 2
• Start date: October 7, 2020
• Completion date: October 31, 2024