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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00984048
• Other study ID #: Q-CROC-01
• Status: Completed
• Start date: August 2009
• Est. completion date: August 2019

Study information

• Verified date: June 2021
• Source: Jewish General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: August 2019
• Est. primary completion date: August 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

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.

Locations

Country	Name	City	State
Belgium	University Hospital Leuven	Leuven
Canada	Hôpital Charles Lemoyne	Greenfield Park	Quebec
Canada	Dr. Georges L. Dumont University Hospital	Moncton	New Brunswick
Canada	The Moncton Hospital	Moncton	New Brunswick
Canada	Hôpital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Hôpital Notre-Dame	Montreal	Quebec
Canada	Hôpital Sacré-Coeur	Montreal	Quebec
Canada	Hôpital Saint-Luc	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	McGill University Health Centre	Montreal	Quebec
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	St-Mary's Hospital	Montreal	Quebec
Canada	Hôtel-Dieu du Québec	Québec	Quebec
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
Jewish General Hospital	Exactis Innovation, Fonds de la Recherche en Santé du Québec, Terry Fox Research Institute

Countries where clinical trial is conducted

Belgium,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of participants with adverse events relating to the liver biopsy procedure		3 years