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

18 Years
Open (Enrolling)
Colorectal Cancer

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Trial Information

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

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 (AvastinĀ®). An
alternative regimen of cytotoxic drugs, also used with AvastinĀ®, 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.

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

8. Abnormal coagulation profile, any anti-coagulant therapy.

9. Known infection with HIV.

Type of Study:


Study Design:

Observational Model: Case-Only, Time Perspective: Prospective

Outcome Measure:

Changes in biomarkers in patients that have acquired clinical resistance.

Outcome Description:

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.

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Gerald Batist, MD

Investigator Role:

Study Director

Investigator Affiliation:

Jewish General Hospital, Segal Cancer Center


Canada: Health Canada

Study ID:




Start Date:

August 2009

Completion Date:

September 2017

Related Keywords:

  • Colorectal Cancer
  • Colorectal cancer
  • Avastin
  • Metastases
  • Liver
  • Colon cancer
  • Biomarkers
  • Resistance
  • Biobanking
  • Colorectal cancer with unresectable metastases to the liver
  • Colorectal Neoplasms