Study of Tumour Response to Tirapazamine During Treatment of Cervical Cancer

February 1, 2012 updated by: British Columbia Cancer Agency

Prospective Study of Tirapazamine Targeting in Cervical Cancer

The purpose of this study is as follows:

  • to determine whether tirapazamine damages cervical tumour DNA immediately after its administration
  • to determine the blood flow and oxygen level of cervical tumour before and after treatment with tirapazamine

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Patients with locally advanced cervical cancer can have a poor clinical outcome with standard cisplatin and pelvic radiation therapy. It is well established that pre-treatment tumor hypoxia is a significant prognostic factor in tumors and may be one of the most important and modifiable mechanisms of radiation resistance in this group of tumours. Significant levels of hypoxia are not present in all locally advanced cervical tumors. Hence measurement of the pretreatment tumour oxygenation status is imperative, and can be assessed using various means. Immunohistochemical staining of various intrinsic hypoxia markers to include Ca9, Glut1, HIF-1 alpha on the pre-treatment tumours can be performed.

Tirapazamine, a bio-reductively activated hypoxic cell selective anti-tumour agent, has been found to act synergistically with cisplatinum, resulting in a significantly higher cell kill than expected based on additive action. We proposed to measure the cell killing effect of tirapazamine with the following tests:

  • Comet assay: Tirapazamine causes DNA damage that can predict for cell killing by measuring DNA damage in cells from tumor biopsies using the alkaline comet assay.
  • Measurement of phosphorylation of histone gamma H2AX: It has been explored as a measure of radiosensitivity in response to clinically relevant doses of radiation. The histone gamma H2AX phosphorylation can be used to detect tirapazamine induced DNA double-strand breaks and collapsed replication forks.

There is some evidence that the drug delivery may be impaired and in fact the drug may not actually be reaching all of the hypoxic tumour cells. A recent study has shown that, in an experimental setting, tirapazamine causes a decrease in vascular perfusion which can be measured with contrast enhanced MRI. We propose to assess if this mechanism is operative in human tumours.

Clinical studies have demonstrated that tumour vascular can increase during the course of radiation therapy, consistent with re-oxygenation and that this is suggestive of a better outcome. Tumours that become less hypoxic during the course of therapy have an increased likelihood of response to the given treatment. However, response to tirapazamine may be reduced. In order to assess both the vascular change that may occur directly because of tirapazamine infusion, as well as any increase in tumour vascularity and perhaps increase in tumour oxygenation during the course of therapy, we plan to assess these tumours during the course of therapy. Assessment of tumour perfusion and vessel permeability after 10 radiation treatments (on day 12) of chemo-radiation therapy will be performed via T1 weighted dynamic contrast enhanced MRI (DCMRI).

We hypothesize that:

  1. Tirapazamine (a hypoxic cell cytotoxin and radiosensitizer) will result in increased DNA damage and a better clinical outcome if:

    1. the pre-treatment tumor demonstrates significant hypoxia
    2. tirapazamine treatment results in increased DNA damage
  2. tirapazamine acts, in part, by changing vascular perfusion in the tumour and that these changes can be measured with dynamic contrast enhanced MRI.

Study Type

Observational

Enrollment (Actual)

1

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
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • British Columbia Cancer Agency, Vancouver Centre

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

Female

Sampling Method

Non-Probability Sample

Study Population

primary care clinic

Description

Inclusion Criteria:

  • Histologically confirmed clinically visible invasive carcinoma of the cervix, either squamous cell, adenocarcinoma or a variant of these
  • Patients must be enrolled in NCIC CXC.1 (phase 3 study assessing the addition of tirapazamine) and randomized to the tirapazamine arm
  • No known bleeding disorder
  • Willing to undergo a clinical exam to obtain tissue biopsy for hypoxia marker analysis and DNA damage assessments

Exclusion Criteria:

  • Inability to give informed consent

  • Criteria below for contrast MRI only :

    1. Chronic renal disease currently on dialysis
    2. Renal insufficiency defined as a Glomerular Filtration Rate (GFR) ≤15cc/min , serum Cr >130, or a BUN>7 measured
    3. Current pacemaker, tens neuro-stimulator, implanted drug infusion devices, any metal implants, foreign metals objects in eyes, aneurysm clips

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

Collaborators and Investigators

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

Sponsor

British Columbia Cancer Agency

Collaborators

Canadian Institutes of Health Research (CIHR)

Investigators

  • Principal Investigator: Christina Aquino-Parsons, MD, British Columbia Cancer Agency

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

August 1, 2007

Study Registration Dates

First Submitted

June 26, 2007

First Submitted That Met QC Criteria

June 26, 2007

First Posted (Estimate)

June 28, 2007

Study Record Updates

Last Update Posted (Estimate)

February 2, 2012

Last Update Submitted That Met QC Criteria

February 1, 2012

Last Verified

February 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TPZ Targeting Cervix Study

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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