The Emergence of RAS Mutations in Metastatic Colorectal Cancer Patients Receiving Cetuximab Treatment

A Non-interventional Uncontrolled Multicenter Study to Investigate the Emergence of RAS Resistance Mutations in RAS Wild Type mCRC Patients Receiving First Line Cetuximab Treatment

To evaluate the emergence of RAS mutation in patients with metastatic colorectal cancer, circulating free DNA will be analyzed using mass spectrometric genotyping in subjects during cetuximab treatment. The hypothesis of this study is that acquired RAS mutation is responsible for the resistance to cetuximab treatment in wild-type colorectal cancer. The usefulness of liquid biopsy to monitor dynamic genetic alterations in colorectal cancer during treatment will also be investigated in this study.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer; Drug Resistance; Mass Spectrometry; RAS-RAF Pathway Deregulation
• Intervention / Treatment: Drug: Cetuximab; Diagnostic test: liquid biopsy

Detailed Description

This is a single arm, non-interventional, uncontrolled, multicenter study in metastatic colorectal cancer patients receiving cetuximab-based infusional 5-FU regimen as 1st line treatment. Patients who are pathologically diagnosed as metastatic colorectal cancer with RAS wild type genotyping will be recruited in this study. Patients enrolled will be those for whom it is planned to treat their colorectal cancer with a cetuximab-based infusional 5-FU regimen according to the locally approved label. Cetuximab-based treatment is anticipated to be continued until disease progression, intolerable toxic effects, or withdrawal of consent occurs. Blood samples from patients enrolled in this study will be collected before the start of cetuximab-based chemotherapy, and every 3 months during the 1st line treatment with the cetuximab-based regimen. Blood sampling is also required at 2-3 weeks after disease progression following cetuximab treatment and after disease progression on 2nd line treatment. The blood samples will be sent to a central laboratory at the Taipei Institute of Pathology and evaluated for RAS genotype, using MassARRAY technique. The objectives of this study are described as follows.

Primary objective:

To observe the percentage of detected RAS mutations (circulating DNA) during 1st line cetuximab exposure in Taiwanese patients.

Secondary objective:

1. To observe the time to onset of detected RAS mutation in circulating DNA.
2. To observe the quantification mutation load change under treatment.
3. To evaluate clinical response and resection rate of metastases with 1st line cetuximab exposure.
4. To evaluate treatment duration with 1st line cetuximab.
5. To investigate the correlation between the occurrence and levels of acquired RAS mutations post-cetuximab treatment and clinical outcomes (progression free survival and overall survival).
6. To calculate total 1st line cetuximab exposure dosage.
7. To investigate correlation between the irinotecan or oxaliplatin dosage and acquired resistance.

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

• Study Contact: Name: Shang Hung Chen, M.D.; Phone Number: 65113 +886-6-7000123; Email: bryanchen@nhri.org.tw

Study Locations

• Taiwan
  • Kaohsiung, Taiwan
    • Recruiting
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
    • Contact: Jaw-Yuan Wang, M.D.; Email: jayuwa@cc.kmu.edu.tw
  • Tainan, Taiwan
    • Recruiting
    • National Cheng Kung University Hospital
    • Contact: Shang Hung Chen, M.D.; Phone Number: 65113 +886-6-7000123; Email: bryanchen@nhri.org.tw
  • Taipei, Taiwan
    • Recruiting
    • Taipei Veterans General Hospital
    • Contact: Jeng-Kai Jiang, M.D.; Email: jkjiang@vghtpe.gov.tw
  • Taipei, Taiwan
    • Not yet recruiting
    • Cathay General Hospital
    • Contact: Yung-Chuan Sung, M.D.; Email: yungchuans@cgh.org.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with RAS wild-type metastatic colorectal cancer receiving cetuximab-based regimen (5-FU containing) as the 1st line treatment.

Description

Inclusion Criteria:

1. Patients with histologically proven metastatic colorectal cancer for whom treatment with cetuximab in 1st line setting, is planned as part of routine clinical practice, as per the locally approved label and the best scientific information; the decision to prescribe cetuximab is at the sole discretion of the investigator. The choice of standard chemotherapy regimen for 1st line treatment of colorectal cancer is also at the sole discretion of the Investigator, based upon routine clinical practice.
2. Patients aged 20 years and above.
3. Patients who are molecularly diagnosed as having RAS wild-type mCRC.
4. Patients who are willing to provide blood samples during the study
5. Patients who are willing, and able and give, signed informed consent.

Exclusion Criteria:

1. Patients having a history of prior exposure to any anti-EGFR therapy.
2. Contra-indications to cetuximab as per locally approved label.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
RAS wild-type colorectal cancer; RAS mutation of patients who are pathologically diagnosed as metastatic colorectal cancer with RAS wild type genotyping will be evaluated using liquid biopsy during cetuximab treatment.	Drug: Cetuximab; Cetuximab-based infusional 5-FU regimen as the 1st line treatment.; Other Names: erbitux; Diagnostic test: liquid biopsy; The blood samples taken from subjects will be evaluated for RAS genotype using MassARRAY technique.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of detected circulating DNA RAS mutations during 1st line cetuximab exposure.	Percentage of detected RAS mutations during cetuximab treatment.	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to onset of newly detected circulating DNA RAS mutation.	Time duration between the start of cetuximab treatment and newly detection of RAS mutation.	9 months
Mutation load (percentage of detected mutated alleles) until disease progression.	Percentage of detected mutated alleles at disease progression.	9 months
Percentage of detected RAS mutations at the time of progression.	Percentage of detected RAS mutations at the time of progression.	9 months
Clinical response rate by the investigator's judgement based on RECIST criteria.	Response rate of tumor after cetuximab treatment.	9 months
Resection rate of liver or lung metastases.	Resection rates of metastases after cetuximab treatment.	9 months
Duration of treatment with cetuximab in 1st line treatment.	Time duration of cetuximab as the 1st line treatment.	9 months
Total accumulated dosage of cetuximab in 1st line treatment.	Total accumulated dosage of cetuximab in 1st line treatment.	9 months
Progression-free survival from start of 1st line treatment with cetuximab.	The time duration of subjects between the inclusion in the study and disease progression.	9 months
Overall survival from the start of 1st line treatment with cetuximab.	The time duration of subjects between the inclusion in the study and death.	24 months

Collaborators and Investigators

• Sponsor: National Health Research Institutes, Taiwan
• Collaborators: Kaohsiung Medical University Chung-Ho Memorial Hospital; Taipei Veterans General Hospital, Taiwan; National Cheng-Kung University Hospital; Cathay General Hospital
• Investigators: Principal Investigator: Li-Tzong Chen, M.D., National Institute of Cancer Research, National Health Research Institutes

Publications and helpful links

General Publications

• Chen SH, Tsai HL, Jiang JK, Sung YC, Huang CW, Yeh YM, Chen LT, Wang JY. Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment: a study protocol. BMC Cancer. 2019 Jun 28;19(1):640. doi: 10.1186/s12885-019-5826-7.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2018
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): January 1, 2022

Study Registration Dates

• First Submitted: January 10, 2018
• First Submitted That Met QC Criteria: January 10, 2018
• First Posted (Actual): January 17, 2018

Study Record Updates

• Last Update Posted (Actual): January 17, 2018
• Last Update Submitted That Met QC Criteria: January 10, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: colorectal cancer; liquid biopsy; RAS mutation; cetuximab resistance
• 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; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: EC1060904

Drug and device information, study documents

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