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

Stage III Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03127111
• Other study ID #: GEDEREFAC-CRC
• Status: Not yet recruiting
• Start date: December 1, 2022
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2022
• Source: Renmin Hospital of Wuhan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 300
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• 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.
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
China	Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University	Wuhan	Hubei

Sponsors (1)

Lead Sponsor	Collaborator
Renmin Hospital of Wuhan University

Country where clinical trial is conducted

China, 

References & Publications (17)

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Jover R, Nguyen TP, Pérez-Carbonell L, Zapater P, Payá A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Reñé JM, Bessa X, Xicola RM, Nicolás-Pérez D, Castells A, Andreu M, Llor X, Boland CR, Goel A. 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology. 2011 Apr;140(4):1174-81. doi: 10.1053/j.gastro.2010.12.035. Epub 2010 Dec 24. — View Citation

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Lin M, Gu J, Eng C, Ellis LM, Hildebrandt MA, Lin J, Huang M, Calin GA, Wang D, Dubois RN, Hawk ET, Wu X. Genetic polymorphisms in MicroRNA-related genes as predictors of clinical outcomes in colorectal adenocarcinoma patients. Clin Cancer Res. 2012 Jul 15;18(14):3982-91. doi: 10.1158/1078-0432.CCR-11-2951. Epub 2012 Jun 1. — View Citation

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Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, Snel MH, Chresta CM, Rosenberg R, Nitsche U, Macarulla T, Capella G, Salazar R, Orphanides G, Wessels LF, Bernards R, Simon IM. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer. 2014 Feb 1;134(3):552-62. doi: 10.1002/ijc.28387. Epub 2013 Sep 13. — View Citation

Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM, Nelson GD, Goldberg RM, Sargent DJ, Alberts SR. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol. 2013 Oct 10;31(29):3664-72. doi: 10.1200/JCO.2013.48.9591. Epub 2013 Sep 9. — View Citation

Sinicrope FA, Shi Q, Smyrk TC, Thibodeau SN, Dienstmann R, Guinney J, Bot BM, Tejpar S, Delorenzi M, Goldberg RM, Mahoney M, Sargent DJ, Alberts SR. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015 Jan;148(1):88-99. doi: 10.1053/j.gastro.2014.09.041. Epub 2014 Oct 8. — View Citation

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Yoon HH, Tougeron D, Shi Q, Alberts SR, Mahoney MR, Nelson GD, Nair SG, Thibodeau SN, Goldberg RM, Sargent DJ, Sinicrope FA; Alliance for Clinical Trials in Oncology. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res. 2014 Jun 1;20(11):3033-43. doi: 10.1158/1078-0432.CCR-13-3140. Epub 2014 Mar 31. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to recurrence (TTR)	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.	3 years after surgery
Secondary	Disease-free survival (DFS)	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.	3 years, 5 years after surgery
Secondary	Cancer-specific survival (CSS)	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.	3 years, 5 years after surgery
Secondary	Overall survival (OS)	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.	3 years, 5 years after surgery