Clinical trial NCT03401957: The Emergence of RAS Mutations in Metastatic Colorectal Cancer Patients Receiving Cetuximab Treatment
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
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Colorectal Cancer
Drug Resistance
Mass Spectrometry
RAS-RAF Pathway Deregulation
Keywords: colorectal cancer
cetuximab resistance
liquid biopsy
RAS mutation
Lead sponsor: National Health Research Institutes, Taiwan
Sponsor class: OTHER
Collaborators: name: National Cheng-Kung University Hospital
name: Kaohsiung Medical University Chung-Ho Memorial Hospital
name: Taipei Veterans General Hospital, Taiwan
name: Cathay General Hospital
First posted: 2018-01-17
Enrollment: 120
Sex: ALL
Minimum age (years): 20
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility 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.

Primary outcomes:
measure: Percentage of detected circulating DNA RAS mutations during 1st line cetuximab exposure.
timeFrame: 9 months
Secondary outcomes:
measure: Time to onset of newly detected circulating DNA RAS mutation.
timeFrame: 9 months
measure: Mutation load (percentage of detected mutated alleles) until disease progression.
timeFrame: 9 months
measure: Percentage of detected RAS mutations at the time of progression.
timeFrame: 9 months
measure: Clinical response rate by the investigator's judgement based on RECIST criteria.
timeFrame: 9 months
measure: Resection rate of liver or lung metastases.
timeFrame: 9 months
measure: Duration of treatment with cetuximab in 1st line treatment.
timeFrame: 9 months
measure: Total accumulated dosage of cetuximab in 1st line treatment.
timeFrame: 9 months
measure: Progression-free survival from start of 1st line treatment with cetuximab.
timeFrame: 9 months
measure: Overall survival from the start of 1st line treatment with cetuximab.
timeFrame: 24 months
Other outcomes:
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Cathay General Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: National Institute of Cancer Research, National Health Research Institutes
name: Li-Tzong Chen, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.