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RAS Mutations in ctDNA and Anti-EGFR reINTROduction in mCRC (RASINTRO) (RASINTRO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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
Sponsor:
Collaborators:
Hôpital Européen George Pompidou, APHP, Paris, France
UMR-S1147, Université Paris Descartes
Methodology and Quality of Life in Oncology Unit, Besançon University Hospital, France
Pitié-Salpêtrière Hospital
Poitiers University Hospital, Poitiers, France
University Hospital Robert Debré, Reims, France
Rennes University Hospital, Rennes, France
Information provided by (Responsible Party):
Association des Gastroentérologues Oncologues

Brief Summary:
Some data have suggested a clinical survival benefit related to the reintroduction of anti-EGFRs therapy in patients with metastatic colorectal cancer (mCRC). Based on resistance mechanisms related to the development of resistant clones, the investigators could assume that patients who benefited most from the reintroduction of anti-EGFRs were those who, through interval chemotherapy, had no longer mutated RAS clone in plasma that appeared during the progression with the first anti-EGFR treatment. Conversely, those who did not benefit from this therapy were probably patients who had mutated RAS clones circulating at the time of reintroduction of anti-EGFRs. To support this hypothesis, investigators propose to evaluate the correlation between the eventual presence of RAS mutations in circulating blood and the efficacy of an anti-EGFR therapy reintroduction in patients with mCRC.

Condition or disease
Metastatic Colorectal Cancer

Detailed Description:

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).

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 73 participants
Observational Model: Cohort
Time Perspective: Prospective
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

Resource links provided by the National Library of Medicine


Group/Cohort
Patients with metastatic colorectal cancer
Rechallenge with an anti-EGFR monoclonal antibody in patients with metastatic colorectal cancer



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with metastatic colorectal cancer receiving a reintroduction of anti-EGFR monoclonal antibody alone (without any associated antitumor drugs)
Criteria

Inclusion Criteria:

  • Age ≥18 years
  • Metastatic colorectal cancer histological confirmed without somatic mutations of KRAS (exons 2, 3 et 4) and NRAS (exons 2, 3 et 4)
  • Apart from contraindication, patients should have already received fluoropyrimidine, irinotecan, oxaliplatin, anti-EGFR (panitumumab or cetuximab) and anti-angiogenic (bevacizumab or aflibercept) therapies
  • Previous treatment with anti-EGFR-based chemotherapy (panitumumab or cetuximab) should have provided an objective tumor response (according to RECIST 1.1 criteria) and/or PFS ≥ 4 months.
  • At least one line of interval chemotherapy between the last cycle of anti-EGFR based treatment and reintroduction of anti-EGFR therapy
  • Signed written informed consent obtained prior to any study specific screening procedures

Exclusion Criteria:

  • Discontinuation of first anti-EGFR therapy for other reasons than tumor progression
  • Previous malignancy other than colorectal cancer in the last 5 years
  • Medical, sociological, psychological or legal conditions that would not permit the patient to sign the informed consent

Information from the National Library of Medicine

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


Contacts
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Contact: Aziz ZAANAN, MD, PhD +33 1 56 09 50 64 ext +33 aziz.zaanan@aphp.fr
Contact: Pierre LAURENT-PUIG, MD, PhD +33 1 42 86 20 72 ext +33 pierre.laurent-puig@parisdescartes.fr

Sponsors and Collaborators
Association des Gastroentérologues Oncologues
Hôpital Européen George Pompidou, APHP, Paris, France
UMR-S1147, Université Paris Descartes
Methodology and Quality of Life in Oncology Unit, Besançon University Hospital, France
Pitié-Salpêtrière Hospital
Poitiers University Hospital, Poitiers, France
University Hospital Robert Debré, Reims, France
Rennes University Hospital, Rennes, France
Investigators
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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
Additional Information:

Publications of Results:

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Responsible Party: Association des Gastroentérologues Oncologues
ClinicalTrials.gov Identifier: NCT03259009    
Other Study ID Numbers: RASINTRO
First Posted: August 23, 2017    Key Record Dates
Last Update Posted: September 11, 2017
Last Verified: September 2017

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Association des Gastroentérologues Oncologues:
colorectal cancer
anti-EGFR therapy
rechallenge
circulating tumor DNA
biomarker
RAS mutations
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases