Primary and Acquired Resistance to Targeted Treatment in BRAF V600E-mutated Metastatic Colorectal Cancer
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age18+
SponsorSwiss Cancer Institute
About this trial
This study prospectively investigates the molecular mechanisms of primary and acquired resistance to standard-of-care BRAF V600E-directed therapy in patients with metastatic colorectal cancer and aims to pre-clinically develop novel strategies to reverse therapy resistance. Clinically approved combination treatment with cetuximab, encorafenib and chemotherapy improves patient outcomes, yet patients eventually experience disease progression. In this prospective multicenter study, tumor tissue, blood, and stool samples will be collected before treatment and at progression, to identify genetic and non-genetic mechanisms of resistance. Additionally, tumor tissue-based in vitro models (patient-derived organoids, PDOs) will be generated and exploited for functional in vitro testing, including genomic and pharmacologic perturbation studies. The overarching goal is to generate knowledge that can help develop new and more effective treatment strategies for future patients.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Diagnosis of unresectable or metastatic BRAF V600E-mutated colorectal cancer
Planned initiation of treatment with combined anti-EGFR antibody and BRAF inhibitor
Patients receiving treatment in any line, with or without chemotherapy
At least one tumor lesion accessible for biopsy
Disqualifiers
Medical or surgical contraindication for tumor biopsy
Active second malignancy (except non-melanoma skin cancer)
Inability to comply with study procedures (e.g., due to language barriers or cognitive impairment)
Pregnancy or breastfeeding
Trial population
Participants will be recruited from oncology centers across Switzerland participating in the Swiss Group for Clinical Cancer Research (SAKK). The study population consists of adult patients with metastatic colorectal cancer treated in routine clinical practice at tertiary care and regional cancer centers. Eligible patients are identified by their treating oncologists at participating sites and enrolled prior to initiation of standard-of-care systemic therapy. Recruitment is limited to centers with access to molecular diagnostics and the capability to perform tumor biopsies and longitudinal sample collection.
Trial design
Design model
Cohort
Time perspective
Prospective
Treatments tested in this trial
Longitudinal translational sampling
Other interventionLongitudinal translational sampling (tumor tissue, plasma ctDNA, stool, PBMCs).
Treatment groups
30 Participants
are divided into 1 treatment groupGroup A: Patients with BRAF V600E-mutated metastatic colorectal cancer1 intervention
Trial outcomes
Primary outcomes
1
Detection rate of molecular alterations associated with acquired resistance
Proportion of patients with detectable molecular alterations associated with acquired resistance to combined BRAF and EGFR inhibition, identified in tumor tissue collected before treatment and at disease progression using molecular profiling.
Time frame
from baseline (pre-treatment) to disease progression (approximately 12 months)Secondary outcomes
1
Detection rate of targetable resistance alterations
Proportion of patients with acquired resistance alterations that are potentially targetable by available or investigational therapies, identified through molecular profiling of tissue and liquid biopsy samples.
Time frame
Baseline to disease progression (approximately 12 months)2
Detection rate of non-genomic resistance mechanisms
Proportion of patients with non-genomic mechanisms of resistance, including transcriptomic changes and tumor microenvironment alterations, identified through molecular analyses.
Time frame
Baseline to disease progression (approximately 12 months)3
Comparison of resistance alterations in tissue versus liquid biopsies
Concordance and detection rates of resistance-associated molecular alterations in matched tumor tissue and circulating tumor DNA samples.
Time frame
Baseline to disease progression (approximately 12 months)4
Establishment rate of patient-derived organoids (PDOs)
Proportion of collected tumor biopsies (baseline and progression) from which patient-derived organoid cultures are successfully established for downstream functional analyses.
Time frame
From baseline biopsy collection through PDO establishment (approximately 3 to 6 months per sample)Sponsors and contacts
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Source ClinicalTrials.gov