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

Prospective Study to Identify Molecular Mechanisms of Clinical Resistance to Standard First-line Therapy in Patients With Metastatic Colorectal Cancer

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: 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
• Enrollment (Actual): 160

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • University Hospital Leuven
• Canada
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • The Moncton Hospital
    • Moncton, New Brunswick, Canada, E1C 8X3
      • Dr. Georges L. Dumont University Hospital
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hôpital Charles Lemoyne
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H3A 1A1
      • Royal Victoria Hospital
    • Montreal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve-Rosemont
    • Montreal, Quebec, Canada, H4A 3J1
      • Mcgill University Health Centre
    • Montreal, Quebec, Canada, H2L 4M1
      • Hôpital Notre-Dame
    • Montreal, Quebec, Canada, H3T 1M5
      • St-Mary's Hospital
    • Montreal, Quebec, Canada, H2X 3J4
      • Hôpital Saint-Luc
    • Montreal, Quebec, Canada
      • Hopital Sacre-Coeur
    • Québec, Quebec, Canada, G1R 2J6
      • Hôtel-Dieu du Québec

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in biomarkers in patients that have acquired clinical resistance.	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	4 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with adverse events relating to the liver biopsy procedure	3 years

Collaborators and Investigators

• Sponsor: Jewish General Hospital
• Collaborators: Exactis Innovation; Fonds de la Recherche en Santé du Québec; Terry Fox Research Institute
• Investigators: Study Director: Gerald Batist, MD, Jewish General Hospital, Segal Cancer Center

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: September 23, 2009
• First Submitted That Met QC Criteria: September 23, 2009
• First Posted (Estimate): September 24, 2009

Study Record Updates

• Last Update Posted (Actual): June 15, 2021
• Last Update Submitted That Met QC Criteria: June 14, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Colorectal cancer; Biomarkers; Resistance; FOLFOX; Avastin; Liver; Colon cancer; Metastases; FOLFIRI; Biobanking; Colorectal cancer with unresectable metastases to the liver
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: Q-CROC-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED