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Primary and Acquired Resistance to Targeted Treatment in BRAF V600E-mutated Metastatic Colorectal Cancer (PARTACER)

15 juli 2026 uppdaterad av: Swiss Cancer Institute

Primary and Acquired Resistance to Targeted Treatment in BRAF V600E-mutated Metastatic Colorectal Cancer (PARTACER-Suisse)

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.

Studieöversikt

Status

Rekrytering

Betingelser

Intervention / Behandling

Detaljerad beskrivning

BRAF V600E-mutated metastatic colorectal cancer accounts for about 8-10% of cases and is an aggressive disease with poor prognosis and limited treatment options. The current standard treatment for patients is the combination of the BRAF inhibitor encorafenib and the anti-EGFR antibody cetuximab, together with FOLFOX or FOLFIRI chemotherapy in 1st line systemic treatment, which improves survival and response rates compared to chemotherapy alone. However, nearly all patients eventually develop resistance to this treatment, and there are no well-established therapies after progression. Resistance develops through complex and often multiple mechanisms, including genetic changes in signaling pathways such as MAPK and receptor tyrosine kinases, as well as non-genomic factors such as changes in gene expression, the tumor microenvironment, and potentially the microbiome. These mechanisms are not yet fully understood, especially in combination and over time during treatment.

This study, PARTACER-Suisse, is a prospective multicenter investigator-initiated study in patients with BRAF V600E-mutated metastatic colorectal cancer receiving standard treatment with encorafenib and cetuximab, with or without concomitant chemotherapy. The study is conducted across a federated network of Swiss oncology centers organized under the Swiss Cancer Center/Swiss Group for Clinical Cancer Research (SCI/SAKK), with a central translational research backbone at the University Hospital Zurich. The aim is to better understand how resistance develops by analyzing tumor samples, blood samples, and stool samples collected before treatment and at disease progression. Blood samples will be used to study circulating tumor DNA over time, and stool samples will allow analysis of the microbiome. Tumor tissue will undergo detailed molecular analyses to identify genetic and non-genetic changes associated with resistance. In addition, tumor samples will be used to generate patient-derived organoids, which are laboratory models that allow functional testing of tumor behavior and response to treatment. By combining molecular analyses with functional experiments, the study aims to identify key resistance mechanisms and explore new treatment strategies that could prevent or overcome resistance.

Overall, this study is expected to provide a more complete understanding of resistance to combined BRAF and EGFR inhibition in this patient population and to support the development of improved and more personalized treatment approaches for the future.

Studietyp

Observationell

Inskrivning (Beräknad)

30

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studiekontakt

Studieorter

  • Schweiz
      • Aarau, Schweiz, CH-5000
        • Rekrytering
        • Kantonsspital Aarau
        • Kontakt:
        • Huvudutredare:
          • Peter Moosmann, MD et phil.
      • Baden, Schweiz, 5404
        • Rekrytering
        • Kantonsspital Baden
        • Kontakt:
        • Huvudutredare:
          • Stefanie Pederiva, MD
      • Basel, Schweiz, 4058
      • Basel, Schweiz, CH-4031
        • Rekrytering
        • Universitaetsspital Basel
        • Kontakt:
        • Huvudutredare:
          • Viviane Prof Hess
      • Bern, Schweiz, 3010
        • Rekrytering
        • Inselspital Bern
        • Kontakt:
        • Huvudutredare:
          • Martin Berger, Prof
      • Biel, Schweiz, 2502
        • Rekrytering
        • Spitalzentrum Biel - MEDIN La Tour
        • Kontakt:
        • Huvudutredare:
          • Emanuel Bührer, MD
      • Chur, Schweiz, 7000
        • Rekrytering
        • Kantonsspital Graubunden
        • Huvudutredare:
          • Sara Bastian, MD
        • Kontakt:
      • Lucerne, Schweiz, 6004
        • Rekrytering
        • Luzerner Kantonsspital
        • Huvudutredare:
          • Simon Häfliger, MD
        • Kontakt:
      • Sankt Gallen, Schweiz, 9007
        • Rekrytering
        • HOCH Health Ostschweiz - Kantonsspital St. Gallen
        • Kontakt:
        • Huvudutredare:
          • Barbara Denecke, MD
      • Solothurn, Schweiz, 4500
        • Rekrytering
        • Bürgerspital Solothurn
        • Kontakt:
        • Huvudutredare:
          • Julian Schardt, MD et phil.
      • Villars-sur-Glâne, Schweiz, 1752
        • Rekrytering
        • HFR Freiburg - Kantonsspital
        • Kontakt:
        • Huvudutredare:
          • Rahel Odermatt, MD
      • Winterthur, Schweiz, 8004
        • Rekrytering
        • Kantonsspital Winterthur
        • Kontakt:
        • Huvudutredare:
          • Guacimara Ortega Sanchez, MD
      • Zurich, Schweiz, 8091
        • Rekrytering
        • Universitätsspital Zürich USZ
        • Huvudutredare:
          • Ralph Fritsch, MD
        • Kontakt:

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

  • Vuxen
  • Äldre vuxen

Tar emot friska volontärer

Nej

Testmetod

Icke-sannolikhetsprov

Studera befolkning

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.

Beskrivning

Inclusion Criteria:

  • 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
  • ECOG performance status 0-2
  • Life expectancy of at least 3 months
  • Age ≥18 years
  • Ability to provide written informed consent

Exclusion Criteria:

  • 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
  • Previous treatment with a BRAF inhibitor

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

Kohorter och interventioner

Grupp / Kohort
Intervention / Behandling
Patients with BRAF V600E-mutated metastatic colorectal cancer
Patients with unresectable or metastatic BRAF V600E-mutated colorectal cancer receiving standard-of-care treatment with combined BRAF and EGFR inhibition (e.g., encorafenib and cetuximab), with or without concomitant chemotherapy. Participants are enrolled prior to treatment initiation and followed longitudinally with collection of tumor tissue, blood, and stool samples to study mechanisms of treatment resistance.
Övrig: Longitudinal translational sampling
Longitudinal translational sampling (tumor tissue, plasma ctDNA, stool, PBMCs).

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Detection rate of molecular alterations associated with acquired resistance
Tidsram: from baseline (pre-treatment) to disease progression (approximately 12 months)
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.
from baseline (pre-treatment) to disease progression (approximately 12 months)

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Detection rate of targetable resistance alterations
Tidsram: Baseline to disease progression (approximately 12 months)
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.
Baseline to disease progression (approximately 12 months)
Detection rate of non-genomic resistance mechanisms
Tidsram: Baseline to disease progression (approximately 12 months)
Proportion of patients with non-genomic mechanisms of resistance, including transcriptomic changes and tumor microenvironment alterations, identified through molecular analyses.
Baseline to disease progression (approximately 12 months)
Comparison of resistance alterations in tissue versus liquid biopsies
Tidsram: Baseline to disease progression (approximately 12 months)
Concordance and detection rates of resistance-associated molecular alterations in matched tumor tissue and circulating tumor DNA samples.
Baseline to disease progression (approximately 12 months)
Establishment rate of patient-derived organoids (PDOs)
Tidsram: From baseline biopsy collection through PDO establishment (approximately 3 to 6 months per sample)
Proportion of collected tumor biopsies (baseline and progression) from which patient-derived organoid cultures are successfully established for downstream functional analyses.
From baseline biopsy collection through PDO establishment (approximately 3 to 6 months per sample)
Longitudinal dynamics of circulating tumor DNA (ctDNA)
Tidsram: Baseline, every 8 to 12 weeks during treatment, and at disease progression (up to approximately 24 months)
Quantitative changes in plasma ctDNA tumor fraction and variant allele frequencies of mutations from baseline through on-treatment time points to progression, and their association with radiological response and resistance evolution.
Baseline, every 8 to 12 weeks during treatment, and at disease progression (up to approximately 24 months)
Compositional characterization of the gut microbiome
Tidsram: Baseline and at disease progression (approximately 12 months)
Compositional and functional features of the gut microbiome at baseline and at disease progression, and their association with treatment response and resistance.
Baseline and at disease progression (approximately 12 months)

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Swiss Cancer Institute

Utredare

  • Studiestol: Ralph Fritsch, MD, University of Zurich

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart (Faktisk)

25 maj 2025

Primärt slutförande (Beräknad)

1 september 2030

Avslutad studie (Beräknad)

1 september 2030

Studieregistreringsdatum

Först inskickad

22 maj 2026

Först inskickad som uppfyllde QC-kriterierna

22 maj 2026

Första postat (Faktisk)

1 juni 2026

Uppdateringar av studier

Senaste uppdatering publicerad (Faktisk)

16 juli 2026

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

15 juli 2026

Senast verifierad

1 juli 2026

Mer information

Termer relaterade till denna studie

Nyckelord

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • SAKK 41/23

Plan för individuella deltagardata (IPD)

Planerar du att dela individuella deltagardata (IPD)?

NEJ

IPD-planbeskrivning

This is a non-interventional observational study with translational research components. Individual participant data sharing is not planned. Aggregate study results, including de-identified molecular and clinical data summaries, will be disseminated through peer-reviewed publications and scientific meetings. De-identified data may be shared with collaborators on a case-by-case basis upon reasonable request to the Study Chair and subject to applicable Swiss data protection regulations, institutional review, and a data-transfer agreement.

Läkemedels- och apparatinformation, studiedokument

Studerar en amerikansk FDA-reglerad läkemedelsprodukt

Nej

Studerar en amerikansk FDA-reglerad produktprodukt

Nej

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