Phase I Evaluation of the Safety of PS 341 in the Treatment of Recurrent Gliomas

Protocol Version: January 20, 2006

Purpose of Study

• To determine the maximum tolerated dose of PS-341 when administered in a twice weekly regimen to adults with recurrent glioma, receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex.
• To describe the biologic activity of PS 341 by this route of administration, by measurement of proteasome 20S activity, and to determine the effects of hepatic enzyme inducing drugs, such as the anticonvulsants on the biologic activity.

Eligibility Criteria

Inclusion Criteria

1. Patients must be 18 years of age or older.
2. Patients must have histologically proven malignant glioma (anaplastic astrocytoma, anaplastic oliogodendroglioma or glioblastoma multiforme) which is progressive or recurrent following radiation therapy +/- chemotherapy. Patients with previous low-grade glioma who progressed after radiotherapy +/- chemotherapy and are biopsied and found to have a high-grade glioma are eligible.
3. Patients must have measurable progressive or recurrent malignant glioma by MRI or CT imaging. (Within two weeks of starting treatment). 
4. Patients must have recovered from toxicity of prior therapy. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy while at least 4 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen.
5. Patients must have no more than one prior chemotherapy regimen. 
6. Patients must have a Karnofsky performance status > 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
7. Patients must have normal hematologic, renal and liver function (i.e. Absolute neutrophil count >1500/mm3, Platelets > 100,000/mm3, Creatinine < 1.7mg/dl, Total Bilirubin < 1.5mg/dl, Transaminases < 4 times above the upper limits of the institutional normal).
8. Patients must be able to provide written informed consent.
9. Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant. Negative pregnancy test for women of childbearing potential. 
10. Patients must have a mini mental score of >15.

Exclusion Criteria

Patients with any of the following are ineligible for this research study:

1. Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment, outlined in this protocol with reasonable safety.
2. Patients who are pregnant or breast-feeding. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant. 
3. Patients may not have had more than one prior chemotherapy treatment. 
4. Patients receiving concurrent investigational agents.
5. Patients who have concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast. Patients with prior malignancies must be disease-free for > five years.

Treatment Schedule

PS 341 is given by vein, over several seconds, twice a week (either on Monday and Thursday or on Tuesday and Friday). The patient will receive PS 341 twice a week for two weeks followed by one week off. The first time that PS 341 is given extra blood samples will be drawn 1, 4 and 24 hours after treatment to check the levels of the drug in the blood.  This means that the patient will need to spend four extra hours in the clinic the first day and return the following day for one more blood sample.  Blood samples will also be drawn every week to see how the patient is tolerating the treatment. An MRI is done every 12 weeks. The patient will continue to receive PS 341 as long as the MRI does not show progression and the therapy does not cause significant toxicity.

Sample Informed Consent

This is a clinical trial (a type of research study). Clinical trials include only patients who choose to take part. Please take your time to make your decision. Discuss it with your friends and family.

You are being asked to take part in this study because you have a brain tumor (glioma) which has grown or recurred.

WHY IS THIS STUDY BEING DONE?

The purpose of this study is to test the safety of an investigational drug, PS 341, and see what effects (good and bad) it has on you and on brain tumors. The study also aims to use different doses of PS 341 in order to find the highest dose that can be given without causing severe side effects.

This research is being done because there are few effective treatments for recurrent gliomas.

PS 341 has been used in animals, where anti-cancer effects have been observed. Human volunteers have also been treated, but only a small number of patients with cancer have received it. Therefore, it is not known if it will slow the growth of human tumors. 

About 42 people will take part in this study.

WHAT IS INVOLVED IN THE STUDY?

If you take part in this study, you will have the following tests and procedures:

You will be tested with blood and urine tests, an electrocardiogram, and a chest x-ray prior to treatment. An MRI or CT scan of the brain will also be performed. The treatment will consist of an intravenous injection of PS 341 (over 3-5 seconds) twice a week for 2 weeks, followed by 1 week without treatment. This 3 week period is called a cycle. Then 2 more weeks of injections will be given in the same schedule. A blood test will be performed weekly (usually 1 or two teaspoons of blood, but once every 6 weeks the test requires 3-4 teaspoons of blood). The brain scan will be repeated after 4 cycles of treatment (11 to 12 weeks after starting). The brain scans (MRI or CT) would be part of routine cancer care. The blood tests are done only as part of this study.

HOW LONG WILL I BE IN THE STUDY? 

PS 341 will be continued on the same schedule unless your tumor grows, or you have side effects that warrant discontinuation, or you desire to stop treatment. You will probably be in the study for a minimum of 12 weeks. The researcher may decide to take you off this study if your doctor thinks it is in your best interest, drug supply is insufficient, your condition worsens, or new information becomes available.

You can stop participating at any time. However, if you decide to stop participating in the study, we encourage you to talk to the researcher and your regular doctor first.

WHAT ARE THE RISKS OF THE STUDY?

While on the study, you are at risk for these side effects. You should discuss these with the researcher and/or your regular doctor. There also may be other side effects that we cannot predict. Other drugs will be given to make side effects less serious and uncomfortable.

 Many side effects are expected to go away shortly after the PS 341 is stopped but in some cases side effects can be serious or long-lasting or permanent.  This is an investigational drug, so that the side effects cannot be fully predicted. 

There are risks to joining this study.  Some, none or all of these side effects are possible.

Likely side effects(> 20% of patients experience these):

• PS 341 may cause a temporary lowering of your blood counts.  If your white blood count becomes low you would be at increased risk for an infection, which could be serious.  If your red blood cell count becomes to low you may experience fatigue or shortness of breath.  If your platelet count becomes too low you would be at risk for bleeding.  Your blood counts will be followed closely while you are being treated.  If your blood counts become to low you may need to spend extra time in the clinic or hospital for the treatment of infections or to receive blood or platelet transfusions.
• Fatigue
• Fever
• Loss of appetite, nausea, vomiting, , diarrhea, constipation
• Abdominal pain
• Headache
• Pain, tingling and/or numbness
• Shortness of breath

 Less likely side effects (≤ 20% of patients experience these):

• Allergic reaction which could include cold-like symptoms (sneezing, stuffiness, sore throat)
• Low blood pressure, malfunction of the heart muscle, fluid collection around the heart
• Cough, hiccoughs, sinus reactions and fluid collection in the lungs
• Dizziness, anxiety, fainting, generalized or localized weakness and/or paralysis
• Swelling of the head, neck and limbs
• Difficulty walking
• Low white blood cell count (which could cause infection)
• Low magnesium in the blood and low phosphate in the blood
• Low blood sugar or high blood sugar
• Rash, itching, flushing and hives
• Irritation at the infusion site
• Insomnia, chills, weight loss
• Dehydration, heartburn, flatulence, obstruction in the bowel, bowel paralysis, mouth sores and taste changes
• Body pain (specifically: muscle, back, bone, throat, chest, joints, arm, leg, and nerve pain)
• Noise in the ears such as clicking, buzzing or thudding
• Dry eyes, double vision or blurred vision
• Abnormalities in your liver or kidney functions, kidney failure
• Nose bleeds, bleeding in the digestive tract, the brain or in the spinal cord

Rare but serious side effects (< 3% of patients experience these):

·        Gastrointestinal ulcer

The intravenous injections and blood sampling may cause local swelling and redness in the vein area of the arm.

Reproductive risks: Because the drugs in this study can affect an unborn baby, you should not become pregnant or father a baby while on this study. You should not nurse your baby while on this study.

Ask about counseling and more information about preventing pregnancy. It is advised that you use a proven form of contraception while on this research study and for 3 months afterwards.   It is possible but unlikely that this drug could cause permanent infertility.

ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 

This drug is being studied to assess its side effects and to determine the best dose for treatment. We do not know if PS 341 will be an effective treatment for this tumor or whether you will experience any benefit from this treatment.
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope the information learned from this study will benefit other patients with glioma in the future.

WHAT OTHER OPTIONS ARE THERE?

Instead of being in this study, you have these options: further surgery, radiation therapy or chemotherapy are sometimes used for relapsed or recurrent brain tumors. Other research options may be available. You can also choose to have no anti cancer therapy, but can ask your doctor to keep you comfortable.

Please talk to your regular doctor about these and other options.

WHAT ABOUT CONFIDENTIALITY?

Efforts will be made to keep your personal information confidential.

We cannot guarantee absolute confidentiality. Your personal information may be disclosed if required by law.

Organizations that may inspect and/or copy your research records for quality assurance and data analysis include groups such as:

• Governmental entities that have the right to see or review your health information, such as the Office of Human Research Protections and the Food and Drug Administration.
• Doctors and staff at other places that are participating in this study
• The sponsor of this study and people that the sponsor my contract with for this study.  The name of the sponsor is CTEP/NCI (National Cancer Institute)
• The Contract Research Office.  The name of the CRO is Theradex.
• The data safety monitoring board
• An outside institutional review board.
• Millennium Pharmaceuticals (the manufacturer of the drug PS 341)
• New Approaches to Brain Tumor Therapy CNS Consortium.

WHAT ARE THE COSTS?

Taking part in this study may lead to added costs to you or your insurance company. Please ask about any expected added costs or insurance problems.
In the case of injury or illness resulting from this study, emergency medical treatment is available but will be provided at the usual charge. No funds have been set aside to compensate you in the event of injury.

You or your insurance company will be charged for continuing medical care and/or hospitalization.

The Division of Cancer Treatment and Diagnosis, NCI, will provide you with the investigational agent free of charge for this study. Should this agent become commercially available or approved for this indication during the course of this study, you may be asked to purchase subsequent doses of the drug needed to complete the study in the event that the company no longer provides the drug to the NCI. You will not be charged for any experimental aspects of this trial (e.g. blood for pharmacokinetics).

You will receive no payment for taking part in this study.

WHAT ARE MY RIGHTS AS A PARTICIPANT?

Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. Leaving the study will not result in any penalty or loss of benefits to which you are entitled. 

We will tell you about new information that may affect your health, welfare, or willingness to stay in this study. 

WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?

For questions about the study or a research-related injury, contact the researcher 

For questions about your rights as a research participant, contact the Institutional Review Board (which is a group of people who review the research to protect your rights).

WHERE CAN I GET MORE INFORMATION?

You may call the NCI's Cancer Information Service at 1 800 4 CANCER
(1 800 422 6237) or TTY: 1 800 332 8615

Visit the NCI's Web sites cancerTrials: comprehensive clinical trials information
http://cancertrials.nci.nih.gov. 

CancerNet: accurate cancer information including PDQ
http://cancernet.nci.nih.gov.