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Genetic and Epigenetic Determinants of Response to Fluorouracil-based Adjuvant Chemotherapy in Patients With Stage III Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT03127111
Recruitment Status : Not yet recruiting
First Posted : April 25, 2017
Last Update Posted : March 15, 2022
Sponsor:
Information provided by (Responsible Party):
Tao Fu, Renmin Hospital of Wuhan University

Tracking Information
First Submitted Date April 16, 2017
First Posted Date April 25, 2017
Last Update Posted Date March 15, 2022
Estimated Study Start Date December 1, 2022
Estimated Primary Completion Date December 31, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 23, 2017)		 Time to recurrence (TTR) [ Time Frame: 3 years after surgery ]
Time to any event, except non-cancer-related death. All recurrences, treatment-related deaths, second same or other primary cancers, and deaths from other cancers are considered to be events. Loss to follow-up and non-cancer-related deaths are censored. Associations between TTR and genetic and epigenetic markers will be analyzed.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: April 23, 2017)
  • Disease-free survival (DFS) [ Time Frame: 3 years, 5 years after surgery ]
    Time to any event, irrespective of cause. All events are included, except loss to follow-up. Associations between DFS and genetic and epigenetic markers will be analyzed.
  • Cancer-specific survival (CSS) [ Time Frame: 3 years, 5 years after surgery ]
    Time to death caused by the same cancer, whether due to the original tumor or to a second primary same cancer. The only event is death from the same cancer, without taking into account whether the death is caused by the primary tumor or a second same cancer. Locoregional recurrence, distant metastases, second primary same cancers, and second other primary cancers are ignored. Deaths from other cancers, non-cancer-related deaths, treatment-related deaths, and loss to follow-up are censored. Associations between CSS and genetic and epigenetic markers will be analyzed.
  • Overall survival (OS) [ Time Frame: 3 years, 5 years after surgery ]
    Time to death, irrespective of cause. There is no need to specify whether the death was due to cancer. Locoregional recurrence, distant metastases, second primary colorectal cancers, and second other primary cancers are ignored. Loss to follow-up is censored. Associations between OS and genetic and epigenetic markers will be analyzed.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Genetic and Epigenetic Determinants of Response to Fluorouracil-based Adjuvant Chemotherapy in Patients With Stage III Colorectal Cancer
Official Title The Identification, Validation and Implementation of Molecular Markers to Predict Response to Fluorouracil-based Adjuvant Chemotherapy in Stage III Colorectal Cancer Patients - Prospective Clinical Observational Study
Brief Summary The goal of this laboratory research is to look for genetic and epigenetic markers that can predict which patients with stage III colorectal cancer will benefit from fluorouracil-based adjuvant chemotherapy.
Detailed Description

This is a prospective project in collecting and assessing clinical outcomes data related to molecular profiling of tumors based on samples from peripheral blood, primary tumor, and adjacent normal colorectal tissue.

Objectives:

  1. Validation of predictive value of known markers CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in the response to 5-fluorouracil-based chemotherapy in patients with stage III colorectal cancer.
  2. Exploratory evaluation of the potential predictive values of known genetic variations including, but not limited to, KRAS mutations, BRAF mutations, PIK3A mutations, and EGFR mutations, etc.
  3. Exploratory identification and evaluation of the predictive value of novel methylation aberrations identified by whole-genome bisulfite sequencing.
  4. Exploratory identification and evaluation of the predictive value of novel genetic aberrations discovered by RNA-sequencing (RNA-seq) or genome-wide association study (GWAS).

Outline:

Blood is collected at baseline and examined for single-nucleotide polymorphisms (SNPs) and expression level of specific gene. Tumor and corresponding normal tissue at surgical resection and assessed for gene methylations, mutations, and expressions.
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Blood, serum, tumor tissue, normal colorectal tissue
Sampling Method Probability Sample
Study Population Patients with histologically confirmed colorectal adenocarcinoma consecutively enrolled at the Department of Gastrointestinal Surgery II, Renmin Hospital, Wuhan University between Jan 2020 and Jan 2025.
Condition Stage III Colorectal Cancer
Intervention
  • Genetic: Gene mutations analysis
    Genomic DNA extracted from paired fresh-frozen tumor and normal tissues is used for KRAS mutations, BRAF mutations, PIK3A mutations, and EGFR mutations, etc., by sequencing and for MSI analysis by PCR and capillary electrophoresis.
  • Genetic: Gene methylation analysis
    Genomic DNA extracted from paired fresh-frozen tumor and normal tissues is used for specific gene methylation or CIMP status analysis by MethyLight or bisulfite sequencing. Whole-genome bisulfite sequencing will be used to identify novel candidate set of predictive markers.
  • Genetic: Gene expression analysis
    RNA extracted from paired fresh-frozen tumor and normal tissues or serum is used for specific gene expression analysis by real-time reverse-transcription PCR (RT-qPCR). RNA-seq will be used to identify novel candidate set of predictive markers.
  • Genetic: SNP analysis
    Genomic DNA extracted from serum is used for specific SNP analysis by using sequencing. GWAS with SNPs array will be used to identify novel candidate set of predictive markers.
  • Genetic: Protein expression analysis
    Tissue microarray made from formalin-fixed paraffin-embedded (FFPE) paired tumor and normal tissues is used for specific protein expression analysis by immunohistochemistry staining.
Study Groups/Cohorts Adjuvant chemotherapy
Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.
Interventions:
  • Genetic: Gene mutations analysis
  • Genetic: Gene methylation analysis
  • Genetic: Gene expression analysis
  • Genetic: SNP analysis
  • Genetic: Protein expression analysis
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Not yet recruiting
Estimated Enrollment
 (submitted: April 23, 2017)		 300
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 31, 2026
Estimated Primary Completion Date December 31, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  1. Requirements for tumor parameters

    1. Histologically confirmed colorectal adenocarcinoma.
    2. Stage III disease (any pT, N1-2, M0).
    3. Tumors must have been curatively resected (R0).
    4. No evidence of residual involved lymph node disease or metastatic disease at the time of registration.

  2. Requirements for patient characteristics

    1. Patient is ≥ 18 years of age on the day of consenting to the study.
    2. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 at the time of screening.
    3. Fertile patients must use effective contraception.
    4. Patients must demonstrate ability to understand and the willingness to sign a written informed consent document.
    5. Patients must demonstrate ability to complete study questionnaires.
    6. Patients must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up.

  3. Required initial laboratory values

    1. Leukocytes ≥ 3,000/mm^3
    2. Absolute neutrophil count ≥ 1,500/mm^3
    3. Platelet count ≥ 100,000/mm^3
    4. Creatinine ≤ 1.5 times upper limit of normal (ULN)
    5. Total Bilirubin ≤ 1.5 times ULN
    6. Aspartate aminotransferase (AST) ≤ 2.5 times ULN
    7. Alanine aminotransferase (ALT) ≤ 2.5 times ULN

Exclusion Criteria:

  1. Patients with a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to fluorouracil.
  2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection-requiring intravenous antibiotics, or psychological, familial, sociological, or geographical condition that would limit compliance with study requirements
  3. Following cardiovascular conditions within the past 6 months: Myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, cerebrovascular accident or transient ischemic attack, deep vein thrombosis, other significant thromboembolic event.
  4. Known human immunodeficiency virus (HIV)-positive patients and those with known hepatitis B or C.
  5. Patients with evidence of other primary malignancies within the past 5 years, excluding adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.
  6. Pregnant or nursing.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts
Listed Location Countries China
Removed Location Countries  
 
Administrative Information
NCT Number NCT03127111
Other Study ID Numbers GEDEREFAC-CRC
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Current Responsible Party Tao Fu, Renmin Hospital of Wuhan University
Original Responsible Party Same as current
Current Study Sponsor Renmin Hospital of Wuhan University
Original Study Sponsor Same as current
Collaborators Not Provided
Investigators Not Provided
PRS Account Renmin Hospital of Wuhan University
Verification Date March 2022