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

September 7, 2017 updated by: Association des Gastroentérologues Oncologues

Predictive Impact of RAS Mutations in Circulating Tumor DNA for Efficacy of Anti-EGFR Reintroduction Treatment in Patients With Metastatic Colorectal Cancer

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.

Study Overview

Status

Unknown

Conditions

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).

Study Type

Observational

Enrollment (Anticipated)

73

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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)

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
The tumor response will be assessed in patients with measurable lesions according to RECIST criteria version 1.1, assessed up to 6 months
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
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Association des Gastroentérologues Oncologues

Collaborators

Pitié-Salpêtrière Hospital
Hôpital Européen George Pompidou, APHP, Paris, France
UMR-S1147, Université Paris Descartes
Methodology and Quality of Life in Oncology Unit, Besançon University Hospital, France
Poitiers University Hospital, Poitiers, France
University Hospital Robert Debré, Reims, France
Rennes University Hospital, Rennes, France

Investigators

  • 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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

October 1, 2017

Primary Completion (Anticipated)

January 1, 2020

Study Completion (Anticipated)

June 1, 2020

Study Registration Dates

First Submitted

August 14, 2017

First Submitted That Met QC Criteria

August 19, 2017

First Posted (Actual)

August 23, 2017

Study Record Updates

Last Update Posted (Actual)

September 11, 2017

Last Update Submitted That Met QC Criteria

September 7, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RASINTRO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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