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Study to Identify Mechanisms of Resistance to Standard Therapy in Patients With Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00984048
Recruitment Status : Recruiting
First Posted : September 24, 2009
Last Update Posted : August 21, 2017
Quebec Clinical Research Organization in Cancer
Terry Fox Research Institute
Fonds de la Recherche en Santé du Québec
Information provided by (Responsible Party):
Gerald Batist, Jewish General Hospital

Brief Summary:
This is a multicenter translational study to understand therapeutic resistance in patients undergoing first-line chemotherapy (FOLFOX/Avastin, or FOLFIRI/Avastin) for metastatic colorectal cancer. Tissue samples from liver metastasis will be collected and banked before the start of chemotherapy and at the time of progression. Additionally, blood samples will be drawn monthly and stored in the tissue biobank.

Condition or disease Intervention/treatment
Colorectal Cancer Other: Needle core biopsies of liver metastasis

Detailed Description:

The major obstacle to the cure of cancer by pharmacological agents is resistance to these agents. Clinical responses of metastatic cancers to the most advanced chemotherapeutic agents usually range from 15 to 40%, indicating that intrinsic resistance, and acquired resistance occurs almost inevitably in those tumors that do respond. In patients with metastatic colorectal cancer, clinical resistance to a particular treatment is a clear endpoint (tumor growth), and is usually observed within 6-12 months of any given therapy. Thus, drug resistance and selecting appropriate therapeutic alternatives for drug-resistant cancer remain major dilemmas for oncologists.

The current first-line treatment for metastatic colorectal cancer in Quebec and much of North America is a combination called FOLFOX (the fluoro-pyrimidine 5-FU given as a 46-hour infusion, folinic acid and oxaliplatin) in combination with bevacizumab (Avastin®). An alternative regimen of cytotoxic drugs, also used with Avastin®, is FOLFIRI, which simply replaces oxaliplatin with the topoisomerase inhibitor irinotecan. In the metastatic setting, studies have not demonstrated significant differences between the two regimens, such that decision-making lacks definitive tools.

The objective of this study is to identify, in clinical samples, the molecular signature of clinically resistant colorectal cancer (CRC) patients for the most current and commonly used therapeutic agents. The goals of this study are two-fold. First, to build a biobank of blood and tissue specimens, prior to starting chemotherapy and at a determined time-point (progression of disease), from patients undergoing the same standard and well established first-line treatments (FOLFOX/bevacizumab or FOLFIRI/bevacizumab) for metastatic colorectal cancer. Second, to use state-of-the-art approaches by various collaborating laboratories to correlate clinical outcomes with molecular events that can be used to predict and circumscribe chemoresistance.

Study Type : Observational
Estimated Enrollment : 180 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Prospective Study to Identify Molecular Mechanisms of Clinical Resistance to Standard First-line Therapy in Patients With Metastatic Colorectal Cancer
Study Start Date : August 2009
Estimated Primary Completion Date : September 2017
Estimated Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab
U.S. FDA Resources

Group/Cohort Intervention/treatment
FOLFOX, XELOX or FOLFIRI +/- bevacizumab
Patients are scheduled to receive first-line treatment for metastatic disease. They should be receiving at least one component of either FOLFOX, XELOX or FOLFIRI regimen with or without bevacizumab.
Other: Needle core biopsies of liver metastasis
No investigational products will be administered to subjects as part of this translational research study. A first-line chemotherapy regimen consisting of FOLFOX, XELOX or FOLFIRI +/- bevacizumab will be administered as per the standard of care at each treating institution. Needle core biopsies of liver metastasis will be collected and banked before the start of chemotherapy and at the time of progression. Additionally, blood samples will be drawn monthly and stored in the tissue biobank.

Primary Outcome Measures :
  1. Changes in biomarkers in patients that have acquired clinical resistance. [ Time Frame: 4 years ]
    Liver needle core biopsies are obtained pre-treatment and at progression of disease from all patients. These are used to discover exploratory biomarkers of resistance to FOLFOX/bevacizumab and FOLFIRI/bevacizumab

Secondary Outcome Measures :
  1. Number of participants with adverse events relating to the liver biopsy procedure [ Time Frame: 3 years ]

Biospecimen Retention:   Samples With DNA
Tumor tissue from a hepatic metastasis will be removed by needle core biopsy (NCB) obtained under radiologic guidance and will be flash-frozen. To obtain sufficient material for tissue banking, three needle core biopsies (NCB) will be removed from the same metastasis. Additionally, monthly whole blood samples will be collected, as well as plasma.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
This study will be conducted in patients with a confirmed diagnosis of colorectal cancer with the presence of liver metastasis, who will be receiving first-line treatment (FOLFOX/bevacizumab or FOLFIRI/bevacizumab) for metastatic disease.

Inclusion Criteria:

  1. Patients with a histologically confirmed diagnosis of colorectal cancer, with at least one liver metastasis site available for biopsy.
  2. For patients with liver only disease, patients deemed not to be initially resectable
  3. Scheduled to receive first-line chemotherapy (FOLFOX/bevacizumab or FOLFIRI/bevacizumab) for metastatic disease.
  4. Measurable metastatic disease (at least one unidimensionally measurable lesion) present after planned biopsy of metastatic site(s).
  5. ECOG 0, 1 or 2.
  6. Life expectancy of 12 or more weeks.
  7. Age > 18 years.
  8. Able to adhere to the study visit schedule and other protocol requirements.
  9. Normal coagulation profile (PT, PTT, INR).

Exclusion Criteria:

  1. Patients with initially resectable liver only metastases
  2. Have received prior therapy for metastatic cancer. Prior adjuvant therapy is allowed.
  3. Inadequate or unusable tissue as the only tissue available for biopsy.
  4. Contraindication to any of the components of the the first-line chemotherapy regimen.
  5. Known brain metastases or meningeal disease.
  6. Female patients who are pregnant or breastfeeding.
  7. Concurrent treatment with other anti-cancer therapy (palliative radiation is allowed but patients must have a metastatic site available for re-biopsy that has not been irradiated).
  8. Abnormal coagulation profile, any anti-coagulant therapy.
  9. Known infection with HIV.

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): NCT00984048

Contact: Mathilde Couetoux du Tertre, PhD 514-282-4523 ext 207 mcouetoux@exactis.ca

University Hospital Leuven Recruiting
Leuven, Belgium
Contact: Bieke Wilmsen    +32 16 340751    bieke.wilmsen@uzleuven.be   
Principal Investigator: Hans Prenen         
Canada, British Columbia
British Columbia Cancer Agency (BCCA) Withdrawn
Vancouver, British Columbia, Canada, V5Z 1H5
Canada, New Brunswick
The Moncton Hospital Recruiting
Moncton, New Brunswick, Canada, E1C 6Z8
Contact: Mrudula Avileli    (506) 857- 5669    Mrudula.Avileli@horizonnb.ca   
Principal Investigator: Mohammed Harb, MD         
Dr. Georges L. Dumont University Hospital Recruiting
Moncton, New Brunswick, Canada, E1C 8X3
Contact: Marie-Eve Gingras    (506) 862-3779    marie-eveg@canceratl.ca   
Principal Investigator: Eve St-Hilaire, MD         
Canada, Ontario
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Contact: Suganthi Suren    (416) 480-5000 ext 82192    suganthi.suren@sunnybrook.ca   
Principal Investigator: Yoo-Joung Ko, MD         
Mount Sinai Hospital Recruiting
Toronto, Ontario, Canada, M5G 1X5
Contact: Janet Smith    416-586-8440    JanetSmith@mtsinai.on.ca   
Principal Investigator: Ronald Burkes, MD         
Canada, Quebec
Hôpital Charles Lemoyne Recruiting
Greenfield Park, Quebec, Canada, J4V 2H1
Contact: Amélie Valcourt    450-466-5000 ext 3373    amelie.valcourt@rrsss16.gouv.qc.ca   
Principal Investigator: Benoit Samson, MD         
Hôpital Maisonneuve-Rosemont Recruiting
Montreal, Quebec, Canada, H1T 2M4
Contact: Darly Cham    514-252-3400 ext 4670    dcham.hmr@ssss.gouv.qc.ca   
Principal Investigator: Lucas Sideris, MD         
Hôpital Notre-Dame Recruiting
Montreal, Quebec, Canada, H2L 4M1
Contact: Annie Lebrasseur    514 890-8000 ext 24831    annie.lebrasseur.chum@ssss.gouv.qc.ca   
Principal Investigator: Mustapha Tefhé, MD         
Hôpital Saint-Luc Active, not recruiting
Montreal, Quebec, Canada, H2X 3J4
Royal Victoria Hospital Recruiting
Montreal, Quebec, Canada, H3A 1A1
Contact: Ayat Salman    514-934-1934 ext 31917    ayat.salman@muhc.mcgill.ca   
Principal Investigator: Peter Metrakos, MD         
Jewish General Hospital Recruiting
Montreal, Quebec, Canada, H3T 1E2
Contact: Claudia Schanz    514-340-8222 ext 23651    cschanz@jgh.mcgill.ca   
Principal Investigator: Gerald Batist, MD         
St-Mary's Hospital Recruiting
Montreal, Quebec, Canada, H3T 1M5
Contact: Rajesh Sharma    514-345-3511 ext 3981    rajesh.sharma.comtl@ssss.gouv.qc.ca   
Principal Investigator: Richard Dalfen, MD         
McGill University Health Centre Recruiting
Montreal, Quebec, Canada, H4A 3J1
Contact: Marie-Claude Joncas    514-934-1934 ext 48186    marie-claude.joncas@muhc.mcgill.ca   
Contact: Linda Chin    514-934-1934 ext 42560    linda.chin@muhc.mcgill.ca   
Principal Investigator: Thierry Alcindor, MD         
Hôpital Sacré-Coeur Recruiting
Montreal, Quebec, Canada
Contact: Caroline Chagnon    514-338-2222 ext 2816    caroline.chagnon@crhsc.rtss.qc.ca   
Principal Investigator: Bernard Lespérance, MD         
Hôtel-Dieu du Québec Recruiting
Québec, Quebec, Canada, G1R 2J6
Contact: Maryse Gingras    418-691-5781    maryse.gingras@chuq.qc.ca   
Contact: Theresa Jones    418-691-1581    theresa.jones@chuq.qc.ca   
Principal Investigator: Felix Couture, MD         
Hopital Fleurimont Withdrawn
Sherbrooke, Quebec, Canada
Sponsors and Collaborators
Jewish General Hospital
Quebec Clinical Research Organization in Cancer
Terry Fox Research Institute
Fonds de la Recherche en Santé du Québec
Study Director: Gerald Batist, MD Jewish General Hospital, Segal Cancer Center

Additional Information:
Responsible Party: Gerald Batist, Principal Investigator, Jewish General Hospital
ClinicalTrials.gov Identifier: NCT00984048     History of Changes
Other Study ID Numbers: Q-CROC-01
First Posted: September 24, 2009    Key Record Dates
Last Update Posted: August 21, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Gerald Batist, Jewish General Hospital:
Colorectal cancer
Colon cancer
Colorectal cancer with unresectable metastases to the liver

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents