Development of a cfDNA 5mC/5hmC-based Biomarker Panel to Predict Targeted Therapy Efficacy in mCRC (EpiDRIVE)

November 3, 2025 updated by: City of Hope Medical Center

Development of a cfDNA 5mC/5hmC-based Epigenetic Biomarker Panel to Identify Determinants of Response In VEGF/EGFR-targeted Therapy for Metastatic Colorectal Cancer

The EpiDRIVE study aims to identify cfDNA-based epigenetic determinants of response in metastatic colorectal cancer (mCRC) patients treated with EGFR- or VEGF-targeted therapy.

By integrating 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiling, this study seeks to develop a predictive biomarker panel capable of differentiating responders from non-responders to targeted therapy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related death. Although targeted agents such as anti-EGFR (cetuximab, panitumumab) and anti-VEGF (bevacizumab) therapies have improved survival, treatment response varies widely even among molecularly defined subgroups.

Traditional biomarkers, including RAS/BRAF mutation and tumor sidedness, fail to accurately predict therapeutic efficacy.

Recent studies highlight the potential of cell-free DNA (cfDNA) methylation (5mC) and hydroxymethylation (5hmC) as sensitive, non-invasive indicators of tumor biology and treatment dynamics.

The EpiDRIVE study integrates cfDNA 5mC/5hmC sequencing and targeted validation to discover and verify epigenetic determinants of therapeutic response.

Discovery phase: Whole-genome 5mC/5hmC profiling to identify differentially modified regions between responders and non-responders.

Training phase: Targeted sequencing to establish a predictive cfDNA epigenetic panel (EpiDRIVE panel).

Validation phase: qPCR-based validation of selected markers in an independent cohort to confirm predictive accuracy.

This study aims to provide a non-invasive biomarker framework to predict and monitor efficacy of EGFR- and VEGF-targeted therapies in mCRC, ultimately guiding personalized treatment selection.

Study Type

Observational

Enrollment (Estimated)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Ajay Goel, PhD
  • Phone Number: 626-359-8111
  • Email: ajgoel@coh.org

Study Locations

  • United States
    • California
      • Duarte, California, United States, 91016
        • Recruiting
        • City of Hope Medical Center
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients diagnosed with Stage IV colorectal adenocarcinoma who received EGFR-targeted or VEGF-targeted therapy and had available pre-treatment plasma samples for cfDNA analysis.

Description

Inclusion Criteria:

  • Histologically confirmed metastatic colorectal adenocarcinoma (mCRC).
  • Received EGFR-targeted therapy (cetuximab/panitumumab) or VEGF-targeted therapy (bevacizumab).
  • Availability of pre-treatment plasma sample for cfDNA analysis.
  • Documented radiologic response evaluation (RECIST 1.1).
  • RAS/BRAF mutation status known.

Exclusion Criteria:

  • Inadequate cfDNA quality or low cfDNA yield.
  • Non-adenocarcinoma histology.
  • Concurrent or prior other active malignancy.
  • Active inflammatory or autoimmune disease affecting cfDNA methylation profiles.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Discovery Cohort - Long PFS Group (Responder)

Patients with metastatic colorectal cancer (mCRC) who received EGFR- or VEGF-targeted therapy and achieved a progression-free survival (PFS) ≥ 12 months, classified as clinical responders.

Pre-treatment plasma cfDNA samples were analyzed by genome-wide 5mC/5hmC sequencing to identify epigenetic determinants associated with durable treatment response.
Diagnostic test: cfDNA 5mC/5hmC Sequencing (EpiDRIVE Discovery Phase)
High-throughput genome-wide sequencing of cfDNA methylation (5mC) and hydroxymethylation (5hmC) profiles from pre-treatment plasma samples in the discovery cohort to identify epigenetic determinants of targeted-therapy response (PFS ≥ 12 months vs < 12 months).
Discovery Cohort - Short PFS Group (Non-Responder)

Patients with mCRC who received EGFR- or VEGF-targeted therapy and showed progression-free survival (PFS) < 12 months, classified as non-responders.

Pre-treatment cfDNA samples were analyzed using genome-wide 5mC/5hmC sequencing and compared with long-PFS responders to identify differential methylation and hydroxymethylation patterns associated with resistance.
Diagnostic test: cfDNA 5mC/5hmC Sequencing (EpiDRIVE Discovery Phase)
High-throughput genome-wide sequencing of cfDNA methylation (5mC) and hydroxymethylation (5hmC) profiles from pre-treatment plasma samples in the discovery cohort to identify epigenetic determinants of targeted-therapy response (PFS ≥ 12 months vs < 12 months).
Training Cohort - Long PFS Group (Responder)

Independent mCRC cohort with PFS ≥ 12 months following EGFR- or VEGF-targeted therapy.

Candidate cfDNA 5mC/5hmC markers identified in the discovery phase were validated using targeted sequencing (EpiDRIVE assay) to construct the predictive epigenetic biomarker panel.
Diagnostic test: EpiDRIVE Assay (Targeted Sequencing / qPCR Validation)
Targeted sequencing or qPCR-based validation of cfDNA 5mC/5hmC markers identified from the discovery phase to develop and validate a predictive biomarker model discriminating patients with long vs short progression-free survival after EGFR-/VEGF-targeted therapy.
Training Cohort - Short PFS Group (Non-Responder)
Independent mCRC patients with PFS < 12 months after targeted therapy. Targeted sequencing using the EpiDRIVE assay was conducted to refine and optimize the predictive model by comparing short- vs long-PFS cases.
Diagnostic test: EpiDRIVE Assay (Targeted Sequencing / qPCR Validation)
Targeted sequencing or qPCR-based validation of cfDNA 5mC/5hmC markers identified from the discovery phase to develop and validate a predictive biomarker model discriminating patients with long vs short progression-free survival after EGFR-/VEGF-targeted therapy.
Validation Cohort - Long PFS Group (Responder)

Separate validation cohort of mCRC patients achieving PFS ≥ 12 months under EGFR- or VEGF-targeted therapy.

qPCR-based EpiDRIVE assay was used to confirm predictive accuracy of the cfDNA 5mC/5hmC biomarker panel in identifying durable responders.
Diagnostic test: EpiDRIVE Assay (Targeted Sequencing / qPCR Validation)
Targeted sequencing or qPCR-based validation of cfDNA 5mC/5hmC markers identified from the discovery phase to develop and validate a predictive biomarker model discriminating patients with long vs short progression-free survival after EGFR-/VEGF-targeted therapy.
Validation Cohort - Short PFS Group (Non-Responder)

Independent validation cohort of mCRC patients with PFS < 12 months after targeted therapy.

cfDNA was analyzed using the qPCR-based EpiDRIVE assay to assess model specificity and distinguish non-responders from long-term responders.
Diagnostic test: EpiDRIVE Assay (Targeted Sequencing / qPCR Validation)
Targeted sequencing or qPCR-based validation of cfDNA 5mC/5hmC markers identified from the discovery phase to develop and validate a predictive biomarker model discriminating patients with long vs short progression-free survival after EGFR-/VEGF-targeted therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-Free Survival (PFS) according to cfDNA 5mC/5hmC biomarker profile
Time Frame: Up to 36 months from therapy initiation
Progression-free survival (PFS) among patients with metastatic colorectal cancer (mCRC) receiving EGFR- or VEGF-targeted therapy, stratified by cfDNA 5mC/5hmC-based biomarker status.
Up to 36 months from therapy initiation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: Up to 60 months from therapy initiation
Time from initiation of EGFR- or VEGF-targeted therapy to death from any cause. Overall survival will be analyzed in relation to cfDNA 5mC/5hmC biomarker-defined groups (high vs low EpiDRIVE score) to assess whether epigenetic cfDNA profiles are associated with differences in survival outcomes.
Up to 60 months from therapy initiation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

City of Hope Medical Center

Investigators

  • Principal Investigator: Ajay Goel, PhD, City of Hope Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 21, 2024

Primary Completion (Estimated)

June 18, 2026

Study Completion (Estimated)

June 18, 2026

Study Registration Dates

First Submitted

November 3, 2025

First Submitted That Met QC Criteria

November 3, 2025

First Posted (Estimated)

November 5, 2025

Study Record Updates

Last Update Posted (Estimated)

November 5, 2025

Last Update Submitted That Met QC Criteria

November 3, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 23228/EpiDRIVE

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Data collected for the study will be made available to others, including de-identified participant data, at publication, via a signed data access agreement and at the discretion of the investigators' approval of the proposed use of such data

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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