A Phase I/II Study of a Recombinant Chimeric Protein Composed of Transforming Growth Factor (TGF - alpha) and a Form of the Pseudomonas Exotoxin Termed PE-38 for the Treatment of Malignant Brain Tumors
What is TP-38?
The purpose of this study is to determine the best dose of the protein TP-38 for the treatment of malignant brain tumors. TP-38 is a protein composed of two parts. One part is called transforming growth factor alpha. This part of the protein binds specifically to brain tumor cells and does not bind to normal brain tissue. The second part of the TP-38 protein is a protein borrowed from the bacterium Pseudomonas. The Pseudomonas exotoxin is a protein secreted by bacteria during an infection, which is highly toxic to cells. By combining these two proteins into the TP-38 molecule we have harnessed the extraordinary potency of the Pseudomonas exotoxin and directed it only at the tumor cells in the brain with a high degree of specificity.
How does TP-38 compare to traditional treatments?
Traditional treatments for malignant brain tumors consist of surgery, radiation, and chemotherapy. The brain tumor program at Duke University Medical Center is actively pursuing many novel agents for brain tumor therapy. TP-38 is an exciting and novel treatment primarily because it differs in several ways from traditional therapy. First of all, it is very specific in its treatment of malignant brain tumors because TP-38 binds only to the tumor cells. TP-38 is also being shown to be very potent. The other advantage of TP-38 therapy includes that it is delivered directly into the brain tumor cavity, which allows delivery of high doses of this anti-tumor drug without producing side effects throughout the body such as nausea, vomiting, and bone marrow suppression. We believe that this local delivery for brain tumor therapy will become the state of the art.
What are the inclusion criteria for the TP-38 study?
In order to be considered eligible for the research study, the patient must meet several inclusion criteria. First, the patient must have a tumor demonstrated on Brain MRI less than 5cm in diameter and the pathology of the tumor must be consistent with a newly diagnosed or recurrent malignant brain tumor or metastatic brain tumor (a tumor which has spread from other parts of the body). The protein on the surface of the cells that binds to TP-38 must also be present. This is determined by a special test done at Duke University on a sample of your tumor from a prior resection or biopsy.
Other inclusion criteria:
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The patient must be 18 years of age or older | |
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The patient must have laboratory tests including a complete blood count with manual differential, coagulation studies, electrolyte panel, liver enzymes, Hepatitis B surface antigen and Hepatitis C antibody, urinalysis, chest xray, electrocardiogram, B-HCG, anticonvulsant levels, and pulmonary function tests within two weeks of the treatment. | |
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No chemotherapy is allowed within four weeks of entry under any circumstances. | |
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The patient must have a Karnofsky Performance Status of at least 60%. |
Criteria which may exclude
a patient from participating in this study:
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Pregnancy or breast feeding | |
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Allergies to local anesthetics or foreign proteins | |
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Tumors involving the brainstem or cerebellum | |
| 4. | Active infection or unexplainable febrile illness | |
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Any form of radiation or chemotherapy within 4 weeks of protocol enrollment |
Please tell me about the TP-38 infusion and procedure.
The entire length of time in the hospital will be approximately 4 days. Throughout your stay, Dr. Sampson or his Nurse Practitioner and a physician from the Brain Tumor Center will visit you daily.
TP-38 is administered by direct infusion into the brain tumor or resection cavity, the area around where part of your brain tumor was removed. Two infusion catheters will be inserted into your tumor or resection cavity. The patient is admitted to the hospital the night before the catheter placement. The catheter placement is a brief surgical procedure that does not require that you get put to sleep. After the operation, you will be admitted to the critical care unit where you will stay for the rest of the time in the hospital. Immediately after surgery the catheters are clamped and no infusion of medication takes place until the following morning. A brain MRI is also obtained that night to confirm the catheter placement.
The TP-38 infusion will begin the next day after catheter placement. TP-38 is infused slowly into your tumor or resection cavity using a pump like the ones used to inject fluids into your veins. The infusion lasts for approximately 2 1/2 days. You will remain in the critical care throughout the infusion. Each morning throughout the treatment you will have blood drawn to monitor laboratory values.
During the time the catheters are in place and the TP-38 is infusing, you will receive an antibiotic to prevent infection and corticosteroids to prevent any brain swelling. Side effects that may occur with this treatment include fever, chills, seizures, cerebral edema, infection, anemia or neurological signs or symptoms such as weakness.
At the end of the infusion, a physician will remove the catheters at the bedside. A MRI will then be obtained to assess the effect of the TP-38 on the tumor. You will be then be discharged home the following day if medically ready.
What dosage of the treatment will I be receiving?
The objective of this research study is to determine the best dose of a specific protein, TP-38, against your malignant brain tumor. Groups of 3-6 patients are treated at the same dose of TP-38. If no adverse effects are noted, the dosage is then increased as per the study protocol. Your specific dosage will be discussed with you before you undergo the treatment.
Do I need to do anything after the TP-38 treatment?
The patient is required to obtain blood tests and MRIs for a total of 60 weeks after the treatment. Blood tests are obtained weekly for eight weeks after the treatment, then at 16 weeks and 24 weeks after the treatment and every 12 weeks thereafter for a year. A Brain MRI is also taken at 4, 8, 16, 24, 36, 48 and 60 weeks after the treatment. The patient will also return to Duke University periodically to visit with Dr. Sampson and a physician from the Brain Tumor Clinic.
Can I repeat the TP-38 infusion in the future?
In other brain tumor protocols, patients have been allowed to repeat treatment with a study drug. However, permission must be obtained from the Federal Drug Association (FDA) before a patient could be treated with TP-38 for a second time.
How is the study going?
TP-38 is a research study and to date fewer than a dozen of patients have been treated. Because only a few patients have been treated and they have been treated recently it is difficult to determine the benefit of TP-38 at this time. We are encouraged by the results we have obtained using TP-38 in animal models where animals have been cured of their brain tumors. We believe that the advantage of this protocol is two fold. First, the infusion technology used to deliver the drug has many advantages. By using a slow infusion we believe we are able to percolate the drug throughout the brain and "hunt down" the tumor cells that have migrated away from the main tumor mass. We liken this to putting logs, which are like the TP-38, in the Mississippi River and allowing them to float down the river in search for tumor cells. The infusion essentially creates small rivers between the normal cells of the brain so that the drug can be carried along these rivers and attack tumor cells that are quite distant from the brain.
The other potential advantage of TP-38 therapy is its incredible specificity. The protein molecule used to bind TP-38 to brain tumor cells only binds the brain tumor cells and binds to no other cells in normal brain tissue. Once it binds to the tumor cells it is internalized or carried into the cell where the pseudomonas exotoxin molecule kills the cells. Because TP-38 needs to be flipped into the cell to cause any cellular damage, it should have the potential to kill tumor cells while leaving normal brain cells unharmed.
TP-38 is also an extremely potent tumor cell killer. Preliminary data indicates that only one molecule of TP-38 is needed to kill a tumor cell. Therefore, very low doses of TP-38 should be highly effective as an anti-tumor agent. We are also extremely enthusiastic about TP-38 therapy given recent results using similar immunotoxins in patients with leukemia. In one study, 11 of 16 patients experienced complete remission of leukemia after the administration of an immunotoxin. At Duke University, using TP-38, we have had one patient who has had greater than 75% shrinkage of her brain tumor, is completely off steroid medications and is without any neurological deficits at this time.
How do I determine if I meet eligibility requirements for the study?
You will be asked to send the most recent Brain MRI, pathology report, pathology tissue blocks from a previous surgery or biopsy, and medical records to Dr. Sampson. Dr. Sampson will review your MRI and clinical condition and determine if you are a candidate for the TP-38 study. If you are then determined a good candidate for the TP-38 study, our pathology department will test your brain tumor cells already in blocks from a previous surgery or biopsy for the presence of the protein on the cells. It the test result is positive, and you meet all other inclusion criteria specified, you may then proceed with the study. If it is negative, you are ineligible to participate in TP-38 but other options may be available to you. In approximately 19 of every 20 patients the brain tumor cells tested for the protein does react with TP-38 and are therefore eligible for this study.
Contact Information
If you are interested in discussing TP-38 further or determining if you qualify for the study, please contact Dr. Sampson at 919-684-9041 or neurosurgeon@mc.duke.edu.
Mailing address:
John H. Sampson, M.D., Ph.D.
4505 Busse Building
4th Floor, Blue Zone
Duke South
Duke University Medical Center
Durham, NC 27710
Fax number: 919-684-9045