Tim[a]
Huntsman Center part of clinical trial on cancer Rx
TransMID drug adheres to cells in brain tumors
By Lois M. Collins
Deseret Morning News
The Huntsman Cancer Institute has enrolled the first patient in a nationwide clinical trial to treat inoperable brain tumors using a medication that sticks to cancer cells and avoids healthy brain tissue.
Traditionally, patients with the malignant tumors, called Glioblastoma Multiforme, have an average life expectancy of less than a year after they´re diagnosed, "despite aggressive therapy," said Dr. Randy Jensen, associate professor of neurosurgery at the U. and one of the clinical investigators. The tumor is "so intrusive it is hard to distinguish from the normal brain tissue. We never get all of them out" in surgery.
If results are positive, Jensen said neurologists hope patients with other conditions, such as Parkinson´s and Alzheimer´s, could benefit as well.
The medication is called TransMID, a modified diphtheria toxin that latches onto transferrin receptors on the cell´s surface. When that happens, the toxin gets into the cells and kills them. But it doesn´t bind to healthy brain cells.
"The hope is that it will selectively kill the tumor cells and leave the normal brain untouched and can potentially cure the brain tumor," he said.
A small catheter is placed into the brain tumor itself and the drug is slowly infused over four or five days, where it spreads throughout the tumor and surrounding brain tissue. The patient is hospitalized for those five days.
The entire process is repeated again a month later.
Current best treatment for the brain tumors includes surgery, then radiation, followed by "some systemic chemotherapies that haven´t worked really well," Jensen said.
For the trial, patients are randomly assigned to the treatment or control group. All receive that standard treatment, but the TransMID is added for patients in the treatment group, who learn the day before surgery. The trial also includes a series of magnetic resonance imaging scans to note the results and whether the tumor shrinks or disappears.
Internationally, about 200 people will be enrolled in the study over the next year. The following year data will be collected and analyzed.
The drug is produced by Xenova Group, a biopharmaceutical company in the United Kingdom that focuses on cancer, addiction treatment and immunotherapy drugs.
The U.S. Food and Drug Administration gave the drug fast track status in August 2001 and orphan drug status in December that year, both recognizing the grave medical prognosis for patients with the high-grade malignant gliomas, the lack of good treatment options and that it is not a common condition.
------
TransMIDTM
Product : TransMIDTM (XR311)
Indication : High-grade glioma (brain cancers)
Design : Modified diphtheria toxin (CRM107) conjugated to transferrin (Tf)
Status : Phase III
TransMIDTM is the most advanced product in Xenova´s pipeline, having entered Phase III clinical trials. TransMIDTM is a treatment for high grade glioma (brain cancer). No efficacious alternatives are currently available for this disease, which has a very poor prognosis. The market opportunity for TransMIDTM has been estimated at $288 m for the lead indication, with an overall market potential of $1.5bn).
Product Overview
TransMIDTM is a modified diphtheria toxin conjugated to transferrin. The diphtheria toxin gains entry to the tumour cell when the transferrin to which it is attached binds to transferrin receptors on the surface of the cells. Transferrin receptors are particularly prevalent on rapidly dividing cells, and the high level of transferrin receptor expression on glioma cells makes transferrin an ideal targeting mechanism for the diseased cells. Once inside a cell the diphtheria toxin interferes with protein synthesis and ultimately kills the cell.
TransMIDTM is pumped directly into the brain tumour via two catheters using CED (Convection Enhanced Delivery - licensed from the National Institute of Health, US). CED greatly enhances the distribution of drugs through the tumour mass and produces high local concentrations of drug. Since TransMIDTM is directly infused into the tumour, it circumvents the usual obstacles presented to drug delivery to the brain by the blood-brain barrier and reduces systemic side effects.
Market
The potential market size for this product in all brain tumour indications is estimated to be $3.8 billion. There are at least 44,000 diagnoses of primary malignant brain tumour made in the US, Europe and Japan each year. At least an additional 220,000 patients will be diagnosed with metastatic brain tumours that originate from cancers elsewhere in the body. Current treatment comprises surgery, external radiotherapy and chemotherapy, although a significant proportion of these tumours are inoperable. Brain cancers are the third leading cause of death in cancer patients younger than 34 years old and the second leading cause of death from cancer in children. Even a small improvement over current treatments represents a significant health benefit.
Clinical Status
Phase I and Phase II clinical trials for TransMIDTM have been completed successfully for the most serious form of malignant brain tumour; high-grade, inoperable gliomas. A Phase I dose-escalating study was performed at the NIH in the US and was followed by a Phase II multi-centre study at nine premier US medical centres. In both Phase I and Phase II studies, treated patients were suffering from inoperable, recurrent high grade gliomas and had failed to respond to all other forms of treatment.
In a Phase II study, a 50% or greater reduction in tumour volume was noted in 35% of evaluable patients, with a corresponding increase in life expectancy in those patients that did respond. Median survival time for responders was 70 weeks, compared to 27 weeks for those that did not respond, which is in line with the average life expectancy for patients treated with the current best standard of care.
In May 2004 Xenova and the FDA reached agreement under the Special Protocol Assessment procedure for the revised Phase III clinical trial programme proposed for TransMIDTM.
Prior to its acquisition by Xenova, KS Biomedix Holdings plc (KS Biomedix) had obtained FDA agreement for a single Phase III clinical trial for TransMIDTM under the SPA process. Following the acquisition of KS Biomedix, Xenova submitted a revised programme involving two smaller sequential Phase III clinical trials rather than one larger study, which has now been agreed with the FDA. The adoption of a two study approach reduces the level of risk associated with a large single study.
The initial Phase III clinical trial is designed to enrol 323 patients with non-resectable, progressive or recurrent Glioblastoma Multiforme (GBM) who have failed conventional therapy. The study will be a randomised, open-labelled, multi-centre trial and will compare TransMIDTM against a number of presently used chemotherapeutic agents regarded as "best standard of care" (BSC). The 323 patients will be randomised in a 2:1 ratio of TransMIDTM:BSC across approximately 50 sites in the EU, Israel and North America.
The primary end-point is overall survival time with a planned interim analysis to be conducted after 50% of the required events have been observed. In an earlier, open label, Phase II study, patients receiving TransMIDTM achieved a significant increase in overall survival compared with historical survival figures. In this study, median survival for patients receiving TransMIDTM was approximately 37 weeks. This compares to the average life expectancy for these patients which is currently approximately 26 weeks.
TransMIDTM is currently licensed to Sosei in Japan, Nycomed in Europe, Medison in Israel and Ranbaxy in India. The rights to TransMIDTM in North America have been retained.