Study of Tumour Response to Tirapazamine During Treatment of Cervical Cancer

Cervix Cancer Clinical Trial

Official title:

Prospective Study of Tirapazamine Targeting in Cervical Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00493376
• Other study ID #: TPZ Targeting Cervix Study
• Status: Terminated
• Phase: N/A
• First received: June 26, 2007
• Last updated: February 1, 2012
• Start date: August 2007

Study information

• Verified date: February 2012
• Source: British Columbia Cancer Agency
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Observational

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Cervix Cancer
• Uterine Cervical Neoplasms

Intervention

Procedure:
• Cervical tissue biopsy analysis: Comet assay
Cervical tissue biopsy analysis: Comet assay
• Biopsy: Measurement of histone gamma H2AX phosphorylation
Biopsy: Measurement of histone gamma H2AX phosphorylation
• Biopsy: Immunohistochemistry: Ca9, Glut1, HIF-1 alpha
Biopsy: Immunohistochemistry: Ca9, Glut1, HIF-1 alpha
• Measurement of vascular perfusion: contrast enhanced MRI
contrast enhanced MRI

Locations

Country	Name	City	State
Canada	British Columbia Cancer Agency, Vancouver Centre	Vancouver	British Columbia

Sponsors (2)

Lead Sponsor	Collaborator
British Columbia Cancer Agency	Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada,