Clinical trial NCT03127111: 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
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Stage III Colorectal Cancer
Lead sponsor: Renmin Hospital of Wuhan University
Sponsor class: OTHER
First posted: 2017-04-25
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Primary outcomes:
measure: Time to recurrence (TTR)
timeFrame: 3 years after surgery
Secondary outcomes:
measure: Disease-free survival (DFS)
timeFrame: 3 years, 5 years after surgery
measure: Cancer-specific survival (CSS)
timeFrame: 3 years, 5 years after surgery
measure: Overall survival (OS)
timeFrame: 3 years, 5 years after surgery
Other outcomes:
Locations:
city: Wuhan
country: China
facility: Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University
state: Hubei
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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.
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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.