The CIRCULATE Spain study: Circulating tumor DNA based decision for adjuvant treatment in localized colon cancer.

Abstract

TPS3635 Background: A substantial proportion of colon cancer (CC) patients do not benefit from adjuvant chemotherapy, and almost 40% of them will develop metastases despite initial optimal treatment. We have designed the phase 2 CIRCULATE-SPAIN trial (EudraCT Number: 2021-000507-2) to prove the feasibility of using liquid biopsy detection of minimal residual disease to guide the post-surgical clinical management of localized CC patients. Moreover, it is important to define if conventional versus intensive adjuvant chemotherapy could convert plasma circulating tumor DNA (ctDNA) positive into a ctDNA negative status. Methods: CIRCULATE-SPAIN is a trial to prove the feasibility of using liquid biopsy detection of MRD to guide the post-surgical clinical management of early colon cancer patients. It is a multicenter, randomized, open-label phase II “Single-To-double ARm Transition (START)” study in which patients are firstly enrolled into a single arm (Phase IIa) study expandable to a randomized double arm (Phase IIb). The CIRCULATE-SPAIN trial involves two primary endpoints, one for the Phase IIa and a second one for the Phase IIb. The primary objective for Phase IIa is to analyze the potential effect of FOLFOXIRI as an intensive adjuvant treatment for ctDNA clearance as a surrogate biomarker of treatment efficacy. Only if the pre-fixed result of 14 out of 40 patients achieves ctDNA clearance, the trial will be expanded to a phase IIb in which patients will be enrolled to randomly receive intensive adjuvant treatment (FOLFOXIRI) versus conventional adjuvant therapy (CAPOX). The primary objective in this phase is to study differences on the conversion rate between both groups. An academic assay based on tumor informed approach is used for ctDNA determination. Tumor and germline samples analysis are carried out by an in-house-developed bioinformatics pipeline specialized in variant-calling analysis using a custom 29-gene panel. Somatic variants are identified by the germline mutations extraction. Different annotation databases and an internal pathological mutation database are used to rule out potential benign somatic variants. Those candidate somatic mutations with the highest allelic frequency are selected and a specific panel of amplicons is designed to monitor their presence in ctDNA using NGS. Plasma samples analysis is carried out by an in-house pipeline specialized in reducing potential background noise. To assess panel performance in both sample types, the bioinformatics pipelines include a set of methods to calculate and filter according to different quality control metrics. Recruitment for the Phase IIa is ongoing with a total of 67 pre-screened out of which two patients were eligible. Clinical trial information: 2021-000. 507-20 .