Role of Circulating Tumour DNA Testing in Assessing for Alterations of Primary Anti-EGFR Resistance in RAS/RAF Wild-type Metastatic Colorectal Cancer Patients

Role of Circulating Tumour DNA (ctDNA) Testing in Assessing for Alterations of Primary Anti-Epidermal Growth Factor Receptor (EGFR) Resistance in RAS/RAF Wild-type Metastatic Colorectal Cancer Patients

The study aims to explore the clinical utility of circulating tumour DNA (ctDNA) in assessing for alterations of anti-epidermal growth factor receptor (EGFR) primary resistance in RAS and BRAF wild-type metastatic colorectal cancer (CRC) patients treated with anti-EGFR monoclonal antibodies (cetuximab / panitumumab) in combination with fluorouracil (FU)-doublet chemotherapy.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer

Detailed Description

A single blood sample (20mL) will be collected after the patient has given informed consent. The blood sample will be collected within 4 weeks prior to the patient starting chemotherapy. Blood samples collected will be processed in accordance with the Guardant360 Clinical Blood Collection Kit instructions (Guardant Health, Inc.).

Patient outcomes with respect to response rate, progression-free survival, overall survival, toxicities and other co-morbid conditions will be ascertained by medical record review conducted by the study personnel. Prospective clinical data that will be collected include: patient demographics, tumor stage and pathological tumor characteristics at diagnosis, laboratory data at diagnosis and serial pre-specified time points, imaging outcomes, chemotherapy information, date of recurrence, and date and cause of death.

Although the data will be censored at the study end-points, the patient's medical record will be reviewed indefinitely to follow the health outcomes.

• Study Type: Observational
• Enrollment (Anticipated): 40

Contacts and Locations

• Study Contact: Name: Cheng Ean Chee

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • National University Hospital
    • Contact: Cheng Ean Chee
    • Principal Investigator: Cheng Ean Chee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with newly diagnosed RAS/BRAF wild-type mCRC who are beginning standard-of-care treatment with fluorouracil-based doublet chemotherapy in combination with anti-EGFR monoclonal antibodies will be recruited into the study. These are patients who are cared for at the National University Cancer Institute, Singapore (NCIS), and identified through the colorectal surgery, medical oncology and multidisciplinary CRC tumour board at NCIS.

Description

Inclusion Criteria:

• Patients with newly diagnosed stage IV colon or rectal cancer who are RAS/BRAF wild-type by routine tumor profiling and who are beginning standard-of-care treatment with fluorouracil-based doublet chemotherapy in combination with anti-EGFR monoclonal antibodies. Prior treatment with adjuvant therapy is allowed if completed more than 6 months prior to relapse of disease.

Exclusion Criteria:

• Pregnant women will be excluded from the study.
• Patient unable to give informed consent will be excluded from the study.
• Patients who have previously received chemotherapy in the metastatic setting.
• Patients who have previously received adjuvant chemotherapy less than 6 months prior to relapse of metastatic disease.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection rate of alterations of anti-epidermal growth factor receptor primary resistance using Circulating tumour DNA	ctDNA analysis will be carried out using Guardant360 platform to identify subgroup of patients who have primary resistance to anti-EGFR therapy.	One timepoint, within 4 weeks prior to starting of anti-EGFR therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	Response rate to treatment received as per standard care.	1 year 6 months
Progression-free survival	The time from commencement of cancer treatment to disease progression or death from any cause.	1 year 6 months
Overall survival	The length of time from start of treatment to death.	1 year 6 months
Adverse reactions experience by patient	Toxicities in patients who have primary resistance to anti-EGFR therapy will be collected and analysed.	1 year 6 months

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore

Publications and helpful links

General Publications

• Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
• Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.
• Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Kohne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Osterlund P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taieb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422. doi: 10.1093/annonc/mdw235. Epub 2016 Jul 5.
• Alix-Panabieres C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016 May;6(5):479-91. doi: 10.1158/2159-8290.CD-15-1483. Epub 2016 Mar 11.
• Vanderlaan PA, Yamaguchi N, Folch E, Boucher DH, Kent MS, Gangadharan SP, Majid A, Goldstein MA, Huberman MS, Kocher ON, Costa DB. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer. Lung Cancer. 2014 Apr;84(1):39-44. doi: 10.1016/j.lungcan.2014.01.013. Epub 2014 Jan 28.
• Krebs MG, Metcalf RL, Carter L, Brady G, Blackhall FH, Dive C. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol. 2014 Mar;11(3):129-44. doi: 10.1038/nrclinonc.2013.253. Epub 2014 Jan 21.
• Morano F, Corallo S, Lonardi S, Raimondi A, Cremolini C, Rimassa L, Murialdo R, Zaniboni A, Sartore-Bianchi A, Tomasello G, Racca P, Clavarezza M, Adamo V, Perrone F, Gloghini A, Tamborini E, Busico A, Martinetti A, Palermo F, Loupakis F, Milione M, Fuca G, Di Bartolomeo M, de Braud F, Pietrantonio F. Negative Hyperselection of Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy. J Clin Oncol. 2019 Nov 20;37(33):3099-3110. doi: 10.1200/JCO.19.01254. Epub 2019 Sep 20.
• Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, Lindeman N, Lockwood CM, Rai AJ, Schilsky RL, Tsimberidou AM, Vasalos P, Billman BL, Oliver TK, Bruinooge SS, Hayes DF, Turner NC. Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol. 2018 Jun 1;36(16):1631-1641. doi: 10.1200/JCO.2017.76.8671. Epub 2018 Mar 5.

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: September 8, 2021
• First Submitted That Met QC Criteria: September 19, 2021
• First Posted (Actual): September 21, 2021

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: ctDNA; anti_EGFR; RAS/RAF wild-type metastatic colorectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: 2020/00339

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No