RAS Mutations in ctDNA and Anti-EGFR reINTROduction in mCRC (RASINTRO) (RASINTRO)
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|ClinicalTrials.gov Identifier: NCT03259009|
Recruitment Status : Unknown
Verified September 2017 by Association des Gastroentérologues Oncologues.
Recruitment status was: Not yet recruiting
First Posted : August 23, 2017
Last Update Posted : September 11, 2017
|Condition or disease|
|Metastatic Colorectal Cancer|
Somatic mutations in KRAS exon 2 are considered as a predictive marker of lack of efficacy for anti-EGFR therapy (panitumumab or cetuximab) in patients with metastatic colorectal cancer. Recently, it has been shown that rare mutations of KRAS (exons 3 or 4) or NRAS (exons 2, 3 and 4) were also predictive for resistance to anti-EGFR antibodies. These data led to a further restriction of anti-EGFR therapy to the subgroup of patients without any RAS mutations.
Emerging RAS mutations in circulating tumor DNA (ctDNA) could be detected in patients with RAS non-mutated colorectal cancer treated with anti-EGFR. The appearance in blood of these rare RAS mutated clones during anti-EGFR therapy was associated with shorter progression free-survival. These results suggest that the growing and development of rare RAS mutated clone, which is probably pre-existing in the primary tumor, may constitute a mechanism of resistance for anti-EGFR therapy.
A phase II prospective study has evaluated the interest of reintroduction of cetuximab in 39 patients previously treated with irinotecan and cetuximab. For inclusion, patients should have had a clinical benefit (stable disease for at least 6 months or clinical response) with the previous line of cetuximab plus irinotecan therapy and then a progression disease for which underwent a new line of chemotherapy before the rechallenge of cetuximab plus irinotecan. The median number of line of chemotherapy before inclusion was 4, and the median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. In this study, the overall response rate was 53.8%, and the median progression free-survival was 6.6 months. No evaluation of circulating tumor DNA was performed in this study.
These data indicate that the colorectal cancer genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockage. It seems that efficacy of anti-EGFR reintroduction could be specifically observed in subgroup of patients who no longer have a RAS mutated clone following the interval chemotherapy.
The aim of this prospective non-interventional study is to evaluate the predictive impact of RAS mutations in circulating tumor DNA for efficacy of anti-EGFR reINTROduction (RASINTRO study) treatment in patients with metastatic colorectal cancer.
The primary endpoint will be the correlation between RAS mutations status in circulating tumor DNA and progression-free survival from the reintroduction of anti-EGFR therapy.
The blood sample for circulating tumor DNA assessment will be carried out in patients who agreed to participate in this observational study just before the first 3 cycles of chemotherapy. This study does not require any additional invasive procedures to those already scheduled for routine care. Indeed, blood sample will be collected from the Huber needle previously implanted in the port-a-cath for chemotherapy perfusion.
After DNA extraction from bood samples, RAS mutation testing will be performed using sequencing with a panel of genes (Ion AmpliSeq Colon and Lung Cancer Panel).
The data related to the patient (age at diagnosis, sex, weight, height, WHO performance status), tumor (tumor markers CEA and CA 19-9, histological type and tumor differentiation, tumor stage, and metastatic sites) and treatment (resection of the primary tumor, date of surgery, lines of chemotherapy, protocol regimen) will be collected anonymously. Monitoring data concern the efficacy of chemotherapy (tumor response, the date of disease progression/death).
|Study Type :||Observational [Patient Registry]|
|Estimated Enrollment :||73 participants|
|Target Follow-Up Duration:||6 Months|
|Official Title:||Predictive Impact of RAS Mutations in Circulating Tumor DNA for Efficacy of Anti-EGFR Reintroduction Treatment in Patients With Metastatic Colorectal Cancer|
|Estimated Study Start Date :||October 1, 2017|
|Estimated Primary Completion Date :||January 1, 2020|
|Estimated Study Completion Date :||June 1, 2020|
Patients with metastatic colorectal cancer
Rechallenge with an anti-EGFR monoclonal antibody in patients with metastatic colorectal cancer
- Progression-free survival (PFS) [ Time Frame: Time from the date of beginning the reintroduction of anti-EGFR therapy to date of tumor progression or death from any cause, whichever occurred first, assessed up to 6 months. ]PFS will be evaluated according to the RAS mutations on circulating tumor DNA status
- Tumor response [ Time Frame: The tumor response will be assessed in patients with measurable lesions according to RECIST criteria version 1.1, assessed up to 6 months ]Tumor response will be evaluated according to the RAS mutations on circulating tumor DNA
- Overall survival (OS) [ Time Frame: Time from the date of beginning the reintroduction of anti- EGFR therapy to date of death of any cause, through study completion, an average of 1 year ]OS will be evaluated according to the RAS mutations on circulating tumor DNA
Biospecimen Retention: Samples With DNA
Circulating tumor DNA
During the inclusion period, a blood sample will be taken just before the first 3 cycles of chemotherapy (C1, C2 and C3) and at tumor progression for mCRC patients treated in one of the participating AGEO centers. These samples will not require any additional invasive procedures since they will be made from the Huber needle previously implanted in the catheter for previously scheduled chemotherapy cycles.
The patient will sign an information letter and a specific informed consent for blood collection and biological studies. In case of specific refusal, the patient will not be included.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03259009
|Contact: Aziz ZAANAN, MD, PhD||+33 1 56 09 50 64 ext +email@example.com|
|Contact: Pierre LAURENT-PUIG, MD, PhD||+33 1 42 86 20 72 ext +firstname.lastname@example.org|
|Principal Investigator:||Aziz ZAANAN, MD, PhD||European Georges Pompidou Hospital, Paris, France|
|Study Chair:||Julien TAIEB, MD, PhD||European Georges Pompidou Hospital, Paris, France|
|Study Director:||Pierre LAURENT-PUIG, MD, PhD||UMR-S1147, Université Paris Descartes, Paris, France|