- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03127111
Genetic and Epigenetic Determinants of Response to Fluorouracil-based Adjuvant Chemotherapy in Patients With Stage III Colorectal Cancer
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
Study Overview
Status
Conditions
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:
- 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.
- 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.
- Exploratory identification and evaluation of the predictive value of novel methylation aberrations identified by whole-genome bisulfite sequencing.
- 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
Enrollment (Anticipated)
Contacts and Locations
Study Locations
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Hubei
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Wuhan, Hubei, China, 430060
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
Requirements for tumor parameters
- Histologically confirmed colorectal adenocarcinoma.
- Stage III disease (any pT, N1-2, M0).
- Tumors must have been curatively resected (R0).
- No evidence of residual involved lymph node disease or metastatic disease at the time of registration.
Requirements for patient characteristics
- Patient is ≥ 18 years of age on the day of consenting to the study.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 at the time of screening.
- Fertile patients must use effective contraception.
- Patients must demonstrate ability to understand and the willingness to sign a written informed consent document.
- Patients must demonstrate ability to complete study questionnaires.
- 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.
Required initial laboratory values
- Leukocytes ≥ 3,000/mm^3
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Creatinine ≤ 1.5 times upper limit of normal (ULN)
- Total Bilirubin ≤ 1.5 times ULN
- Aspartate aminotransferase (AST) ≤ 2.5 times ULN
- Alanine aminotransferase (ALT) ≤ 2.5 times ULN
Exclusion Criteria:
- Patients with a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to fluorouracil.
- 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
- 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.
- Known human immunodeficiency virus (HIV)-positive patients and those with known hepatitis B or C.
- 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.
- Pregnant or nursing.
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
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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.
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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.
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.
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.
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.
Tissue microarray made from formalin-fixed paraffin-embedded (FFPE) paired tumor and normal tissues is used for specific protein expression analysis by immunohistochemistry staining.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Time to recurrence (TTR)
Time Frame: 3 years after surgery
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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.
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3 years after surgery
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Disease-free survival (DFS)
Time Frame: 3 years, 5 years after surgery
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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.
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3 years, 5 years after surgery
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Cancer-specific survival (CSS)
Time Frame: 3 years, 5 years after surgery
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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.
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3 years, 5 years after surgery
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Overall survival (OS)
Time Frame: 3 years, 5 years after surgery
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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.
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3 years, 5 years after surgery
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Collaborators and Investigators
Publications and helpful links
General Publications
- Punt CJ, Buyse M, Kohne CH, Hohenberger P, Labianca R, Schmoll HJ, Pahlman L, Sobrero A, Douillard JY. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. J Natl Cancer Inst. 2007 Jul 4;99(13):998-1003. doi: 10.1093/jnci/djm024. Epub 2007 Jun 27.
- Jover R, Nguyen TP, Perez-Carbonell L, Zapater P, Paya A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Rene JM, Bessa X, Xicola RM, Nicolas-Perez 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.
- Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004 Feb;126(2):394-401. doi: 10.1053/j.gastro.2003.12.023.
- Gamazon ER, Huang RS, Cox NJ, Dolan ME. Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9287-92. doi: 10.1073/pnas.1001827107. Epub 2010 May 4.
- Dai J, Gu J, Huang M, Eng C, Kopetz ES, Ellis LM, Hawk E, Wu X. GWAS-identified colorectal cancer susceptibility loci associated with clinical outcomes. Carcinogenesis. 2012 Jul;33(7):1327-31. doi: 10.1093/carcin/bgs147. Epub 2012 Apr 12.
- Xing J, Myers RE, He X, Qu F, Zhou F, Ma X, Hyslop T, Bao G, Wan S, Yang H, Chen Z. GWAS-identified colorectal cancer susceptibility locus associates with disease prognosis. Eur J Cancer. 2011 Jul;47(11):1699-707. doi: 10.1016/j.ejca.2011.02.004. Epub 2011 Mar 12.
- 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.
- O'Donnell PH, Stark AL, Gamazon ER, Wheeler HE, McIlwee BE, Gorsic L, Im HK, Huang RS, Cox NJ, Dolan ME. Identification of novel germline polymorphisms governing capecitabine sensitivity. Cancer. 2012 Aug 15;118(16):4063-73. doi: 10.1002/cncr.26737. Epub 2012 Jan 3.
- 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.
- 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.
- Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgo E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med. 2016 Jan 21;374(3):211-22. doi: 10.1056/NEJMoa1506597.
- 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.
- 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.
- Toiyama Y, Hur K, Tanaka K, Inoue Y, Kusunoki M, Boland CR, Goel A. Serum miR-200c is a novel prognostic and metastasis-predictive biomarker in patients with colorectal cancer. Ann Surg. 2014 Apr;259(4):735-43. doi: 10.1097/SLA.0b013e3182a6909d.
- Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D, Cortina C, Morral C, Barcelo C, Tosi S, Riera A, Attolini CS, Rossell D, Sancho E, Batlle E. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015 Apr;47(4):320-9. doi: 10.1038/ng.3225. Epub 2015 Feb 23.
- Kap EJ, Seibold P, Scherer D, Habermann N, Balavarca Y, Jansen L, Zucknick M, Becker N, Hoffmeister M, Ulrich A, Benner A, Ulrich CM, Burwinkel B, Brenner H, Chang-Claude J. SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients. Int J Cancer. 2016 Jun 15;138(12):2993-3001. doi: 10.1002/ijc.30026. Epub 2016 Feb 19.
- Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017 Mar 23;17(4):268. doi: 10.1038/nrc.2017.24. No abstract available.
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- GEDEREFAC-CRC
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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