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

• ClinicalTrials.gov Identifier: NCT03401957
• Recruitment Status: Recruiting
• First Posted: January 17, 2018
• Last Update Posted: January 17, 2018
• Sponsor: National Health Research Institutes, Taiwan
• Collaborators: National Cheng-Kung University Hospital; Kaohsiung Medical University Chung-Ho Memorial Hospital; Taipei Veterans General Hospital, Taiwan; Cathay General Hospital
• Information provided by (Responsible Party): National Health Research Institutes, Taiwan

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Colorectal Cancer; Drug Resistance; Mass Spectrometry; RAS-RAF Pathway Deregulation	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 Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 120 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 18 Months
• Official Title: 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
• Estimated Study Start Date: January 2018
• Estimated Primary Completion Date: January 2022
• Estimated Study Completion Date: January 2022

Groups and Cohorts

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 Name: erbitux; Diagnostic Test: liquid biopsy; The blood samples taken from subjects will be evaluated for RAS genotype using MassARRAY technique.

Outcome Measures

Primary Outcome Measures :

1. Percentage of detected circulating DNA RAS mutations during 1st line cetuximab exposure. [ Time Frame: 9 months ]
   Percentage of detected RAS mutations during cetuximab treatment.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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.

Contacts and Locations

Contacts

Contact: Shang Hung Chen, M.D.; +886-6-7000123 ext 65113; bryanchen@nhri.org.tw

Locations

Taiwan

Kaohsiung Medical University Chung-Ho Memorial Hospital; Recruiting

Kaohsiung, Taiwan

Contact: Jaw-Yuan Wang, M.D. jayuwa@cc.kmu.edu.tw

National Cheng Kung University Hospital; Recruiting

Tainan, Taiwan

Contact: Shang Hung Chen, M.D. +886-6-7000123 ext 65113 bryanchen@nhri.org.tw

Cathay General Hospital; Not yet recruiting

Taipei, Taiwan

Contact: Yung-Chuan Sung, M.D. yungchuans@cgh.org.tw

Taipei Veterans General Hospital; Recruiting

Taipei, Taiwan

Contact: Jeng-Kai Jiang, M.D. jkjiang@vghtpe.gov.tw

Sponsors and Collaborators

National Health Research Institutes, Taiwan

National Cheng-Kung University Hospital

Kaohsiung Medical University Chung-Ho Memorial Hospital

Taipei Veterans General Hospital, Taiwan

Cathay General Hospital

Investigators

• Principal Investigator: Li-Tzong Chen, M.D.; National Institute of Cancer Research, National Health Research Institutes

More Information

Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: National Health Research Institutes, Taiwan
• ClinicalTrials.gov Identifier: NCT03401957
• Other Study ID Numbers: EC1060904
• First Posted: January 17, 2018
• Last Update Posted: January 17, 2018
• Last Verified: January 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Health Research Institutes, Taiwan:

colorectal cancer; cetuximab resistance; liquid biopsy; RAS mutation

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Cetuximab; Antineoplastic Agents, Immunological; Antineoplastic Agents