Study to Identify Biomarkers of Clinical Response to Aflibercept in Patients With Metastatic Colorectal Cancer

November 15, 2016 updated by: CR-CSSS Champlain-Charles-Le Moyne

A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Aflibercept in Patients With Metastatic Colorectal Cancer Who Have Failed First-Line Therapy

This is a Phase II multi-center exploratory study to identify biomarkers predictive of clinical response to aflibercept in patients with metastatic colorectal cancer who have failed first-line therapy, consisting of an oxaliplatin-containing regimen in combination with bevacizumab. Patients will consent to a needle core biopsy of a liver metastatic lesion prior to starting treatment and blood samples will be collected from study patients during treatment.

An exploratory pharmacoeconomic analysis will be performed to evaluate productivity loss, quality of life and resource utilization while on treatment with aflibercept.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This is a Phase II multi-center exploratory study to identify biomarkers predictive of clinical response to aflibercept in patients with metastatic colorectal cancer who have failed first-line therapy, consisting of an oxaliplatin-containing regimen in combination with bevacizumab. Patients will consent to a needle core biopsy of a liver metastatic lesion prior to starting treatment. This study will be open primarily at sites conducting the Q-CROC-01 study (NCT00984048), in which colorectal cancer patients receiving standard first-line treatment undergo a biopsy of a liver metastatic lesion before treatment and at resistance. The post-first-line treatment biopsy will be used as the pre-treatment biopsy for this trial. For patients not participating in the Q-CROC-01 study, patients will be required to undergo a liver needle core biopsy of a metastatic lesion before study treatment.

Biopsies and blood samples will be collected from all study patients. An exploratory pharmacoeconomic analysis will be performed to evaluate productivity loss, quality of life and resource utilization while on treatment with aflibercept.

A total of 52 patients will be enrolled, primarily at centers participating in the Q-CROC-01 study. The trial will close enrolment when 42 evaluable pre-treatment tumor biopsy samples have been obtained. Accrual of the total patient population is estimated to take 24-36 months with the estimated start date being February 2014.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Phase 2

Contacts and Locations

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

Study Locations

  • Canada
    • Quebec
      • Greenfield Park, Quebec, Canada, J4V 2H1
        • CSSS Champlain-Charles-Le Moyne
      • Montreal, Quebec, Canada, H3T 1E2
        • Jewish General Hospital
      • Montreal, Quebec, Canada, H1T 2M4
        • Hopital Maisonneuve-Rosemont
      • Montréal, Quebec, Canada, H4J 1C5
        • Hôpital du Sacré-Coeur de Montréal

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

Description

Inclusion Criteria:

  1. Histologically or cytologically proven adenocarcinoma of the colon or rectum, with at least one liver metastasis site available for biopsy.
  2. Patients must have received only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy must be an oxaliplatin containing regimen (in combination with bevacizumab). Patients who did not receive bevacizumab in their first-line treatment regimen may also be considered.
  3. Metastatic disease that is not amenable to potentially curative treatment.
  4. Measurable metastatic disease and evaluable disease.
  5. ECOG 0 or 1.
  6. Normal coagulation profile (PT, PTT, INR).
  7. Provide written consent after the investigational nature, study design, risks and benefits of the study have been explained.
  8. Age ≥ 18 years.

Exclusion Criteria:

  1. More than 1 prior chemotherapy regimen for metastatic colorectal cancer. Previous adjuvant FOLFOX based chemotherapy is allowed.
  2. Relapse from adjuvant treatment within 6 month of completion of adjuvant chemotherapy.
  3. Less than 42 days elapsed from prior major surgery to the time of registration.
  4. Inadequate or unusable tissue as the only tissue available for biopsy.
  5. Any of the following within 3 months of registration: Grade 3-4 gastrointestinal bleeding/hemorrhage, diverticulitis, pulmonary embolism, inflammatory or infections bowel disease, treatment resistant peptic ulcer disease, colitis, erosive esophagitis or gastritis, uncontrolled thromboembolic event.
  6. Prior intolerance to bevacizumab due to toxicity.
  7. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
  8. Gilbert's Syndrome.
  9. Occurrence of deep vein thrombosis within 4 weeks, prior to registration.
  10. Any of the following within 6 months prior to registration; myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack.
  11. Contraindication to any of the components of the FOLFIRI chemotherapy regimen, as per investigators' judgement.

  12. Inadequate bone marrow function as follows:

    • Absolute neutrophil count (ANC) < 1.5x 109/L
    • Platelet count < 100 x 109/L
    • Hemoglobin < 90 g/L

  13. Inadequate liver function test:

    • Total bilirubin > 1.5 x ULN
    • Transaminases > 3 x ULN (if liver metastasis are present, 5 x ULN)
    • Alkaline phosphatase > 3 x ULN (if liver metastases are present, 5 x ULN)

  14. Contraindication to aflibercept. Including:

    • Urine protein-creatinine ratio (UPCR) > 1 on morning spot urinalysis or proteinuria >500 mg/24-h
    • Serum creatinine > 1.5 x upper limit of normal (ULN). If creatinine 1.0 - 1.5 x ULN, creatinine clearance, calculated according to Cockroft-Gault formula, < 60 ml/min will exclude the patient.
    • History of uncontrolled hypertension, defined as blood pressure > 150/100 mgHG (grade ≥ 2 according to NCIC CTCAE v. 4.0), or systolic blood pressure > 180 mmHG when diastolic blood pressure < 90 mmHG, on at least 2 repeated determinations on separate days within 3 months prior to study enrollment.
    • Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-or-therapeutic range INR (>3) within the 4 weeks prior to study entry.
    • Evidence of clinically significant bleeding diathesis or underlying coagulopathy (eg. INR>1.5 without vitamin K antagonist therapy), non-healing wound.
  15. Known active brain metastases or meningeal disease.
  16. Female patients who are pregnant or breastfeeding.
  17. Patients of reproductive potential (male and female) who do not agree to use an accepted form of contraception during the study period and up to 6 months following completion of study treatment.
  18. Concurrent treatment with other anti-cancer therapy (palliative radiation is allowed but patients must have a metastatic site available for biopsy that has not been irradiated).
  19. Known infection with HIV.

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

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: aflibercept and FOLFIRI
Drug: aflibercept + FOLFIRI
Aflibercept (Sanofi and Regeneron) targets the Vascular endothelial growth factor (VEGF) pathway that is a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. In pre-clinical assessments, aflibercept results in stronger angiogenesis inhibition than bevacizumab, exhibiting at least 100-1000 times higher affinity to the circulating VEGFs. It is postulated that in vivo, the binding of these ligands to aflibercept results in the blockade of tumor angiogenesis along with pruning of existing tumor vascular elements and reduction of VEGF-driven vascular permeability. The expected outcome is reduced growth of primary and metastatic tumors by impeding the density of tumor vasculature and diminishing the abnormal leakiness of tumor vessels that supply matrix components to the cancer.
Other Names:
  • aflibercept
  • FOLFIRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
A biomarker (in blood or tissue) that may be predictive of level of response to aflibercept
Time Frame: 3 years
A biopsy from a liver metastasis will be taken at baseline for discovery of biomarkers that correlate with response to aflibercept. Genomic material (DNA and RNA) will be isolated from all biopsies. Batched analysis will be performed at the end of the study with the evaluable samples for multiplex biomarker discovery. Patient's biomarker status at baseline will be correlated with treatment effect on PFS and response (including response rate and disease control rate) to explore which biological targets may be particularly important in defining the appropriate treatment population for aflibercept.
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression free survival (PFS)
Time Frame: Time from registration to progressive disease (up to 3 years)
The time from the date of registration until the date of radiological disease progression assessed by RECIST 1.1 or until death due to any cause, even in the absence of radiological progression.
Time from registration to progressive disease (up to 3 years)
Response rate
Time Frame: 3 years
Defined as complete response (CR) and partial response (PR)
3 years
Disease control rate
Time Frame: 3 years
Defined as complete response (CR) + partial response (PR) + stable disease (SD).
3 years
Number of participants with adverse events
Time Frame: 3 years
Assessment of safety profile of aflibercept in combination with FOLFIRI: report of Adverse Events according to the NCI's Common Toxicity Criteria version 4.0
3 years
The quality of life impact of treating with FOLFIRI in combination with Aflibercept
Time Frame: From date of registration until progression of disease assessed up to 36 months
Quality of life will be evaluated by questionnaires completed by the patient.
From date of registration until progression of disease assessed up to 36 months

Collaborators and Investigators

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

Sponsor

CR-CSSS Champlain-Charles-Le Moyne

Collaborators

Sanofi
Regeneron Pharmaceuticals
Quebec Clinical Research Organization in Cancer

Investigators

  • Principal Investigator: Benoit Samson, MD, CSSS Champlain-Charles-Le Moyne

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

January 1, 2014

Primary Completion (Actual)

November 1, 2016

Study Completion (Actual)

November 1, 2016

Study Registration Dates

First Submitted

January 20, 2014

First Submitted That Met QC Criteria

January 23, 2014

First Posted (Estimate)

January 24, 2014

Study Record Updates

Last Update Posted (Estimate)

November 16, 2016

Last Update Submitted That Met QC Criteria

November 15, 2016

Last Verified

August 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Q-CROC-04

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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