A PHASE I, OPEN-LABEL, NON-RANDOMIZED, MULTICENTER, SINGLE AGENT STUDY OF INTRAVENOUS SDX-102 FOR THE TREATMENT OF PATIENTS WITH MTAP-DEFICIENT HIGH GRADE RECURRENT MALIGNANT GLIOMAS

Protocol Version: October 5, 2005

Purpose of Study

• To determine the maximum tolerated dose (MTD) of SDX-102 administered as a continuous 5 day infusion 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 characterize the pharmacokinetic activity of SDX-102 concurrently administered with EIAEDs (Enzyme-Inducible Anti-Epileptic Drugs).

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 oligodendroglioma 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 documented absense of MTAP on fixed tumor specimens.

5. 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 3 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.

6. Patients must have a Karnofsky performance status ³ 60.

7. Patients must have normal hematologic, renal and liver function (i.e. absolute neutrophil count ³1500/mm³, Platelets ³ 100,000/mm³, serum creatinine £ 1.5mg/dl, total bilirubin £ 1.5mg/dl, transaminases £ 4 times above the upper limits of the institutional norm).

8. Patients must be able to provide written informed consent.

9. Patients must have no more than 2 prior drug regimens.

10. Female patients of childbearing potential must have a negative pregnancy test (serum b-HCG); both male and female patients must employ effective contraceptive measures prior to start of therapy until four weeks after the last dose of study drug.  Oral contraceptives alone are not considered adequate for this study.  Barrier methods of contraception and abstinence are adequate.

11. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast.  Patients with prior malignancies must be disease-free for ³ five years.

12. Patients must be maintained on a stable or lower corticosteroid regimen from the time of their baseline scan until the start of treatment.

13. Patients must have a Mini Mental State Exam score of ³ 15

Exclusion Criteria

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

2. 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.

3. Patients who are pregnant or breast-feeding.

4. Patients with more than 2 prior treatment regimens.

5. Patients receiving concurrent investigational agents.

6. Patients who have psychological or sociological conditions, addictive disorders or family problems, which would preclude compliance with the protocol.

Treatment Schedule

This is a phase I open-label, non-randomized, multi-center, single agent study of intravenous SDX-102 for the treatment of patients with MTAP-deficient, recurrent glioblastoma multiforme, anaplastic astrocytoma, and anaplastic oligodendroglioma.  Patients will be screened for the absence of MTAP prior to the start of SDX-102 infusions.  Fixed tumor specimens will be sent to Genzyme Genetics Analytical Services for MTAP determination.   Patients meeting all eligibility requirements will be enrolled on study. 

The starting dose for dose escalation will be 80 mg/m² daily for 5 days.  SDX-102 will be given intravenously as a continuous infusion for 5 days repeated every 21 days.

Sample Informed Consent

The MTAP Screening Consent

Phase I, Open-Label, Non-Randomized, Multicenter, Single Agent Study of Intravenous SDX-102 for the Treatment of Patients with MTAP-Deficient High Grade Recurrent Malignant Glioma

  WHY IS THIS STUDY BEING DONE?

 This research is being done because currently, there is no highly effective long-term treatment for your type of cancer.  Glioblastoma multiforme is a type of brain tumor that is almost never cured with surgery, radiation or chemotherapy.

 This study uses an investigational anti-cancer drug called SDX-102.  Investigational means that SDX-102 has not been approved by the U.S. Food and Drug Administration (FDA).  SDX‑102 may be active in many types of cancer.  SDX-102 is only active on tumor cells in which the MTAP gene is deleted. 

 For that reason this study will only include patients whose tumors do not have the MTAP gene.  To be considered for this study your brain tumor tissue must first be tested to see if the MTAP gene is missing.  This test will be done on a sample of tumor that was taken during your last surgery.  This sample will be sent to a lab for examination.  It will be tested for the MTAP gene.  If you tumor tissue does NOT have the MTAP gene you may continue to be screened for eligibility.  If your tissue does have the MTAP gene you may NOT join this study.  Your doctor will discuss other treatment options with you.  

Your signature on this document only authorizes the testing of your tumor tissue for the MTAP gene.  You will need to sign a different consent for further eligibility testing and possible treatment with SDX-102.  To the extent possible, your confidentiality will be maintained, as your tumor sample will not be identified with your name or social security number.

 What are the risks of having your tumor tissue tested?

 There are no risks to you in having your tumor tested for the MTAP gene.  We will use tissue samples remaining from your last surgery.

 Are there benefits to having your tumor tissue tested?

 By testing your tumor tissue we will find out if you have the MTAP gene. 

 Will it cost you anything to have your tumor tissue tested?

 There will be no costs to you or your insurance company to have your tissue tested. 

 Will you be paid if you have your tumor tested?

 You will receive no payment for having your tumor tested.

 What are other options are there?

 You do not have to have your tumor tested. 

 Is having my tumor tissue tested voluntary?

·                    Participation is voluntary.

·                    If you wish to stop, please tell us right away.

WHAT ABOUT CONFIDENTIALITY?

 Federal regulations give you certain rights related to your health information.  These include the right to know who will be able to get the information and why they may be able to get it.  The study doctor must get your authorization (permission) to use or give out any health information that might identify you.

 What information may be used and given to others?

If you choose to be in this study, the study doctor will get personal information about you and the results of the testing done on your sample.

 Who may use and give out information about you?

Information about your health may be used and given to others by the study doctor and staff.

 Who might get this information?

Your information may be given to the sponsor of this research.  “Sponsor” includes any persons or companies that are working for or with the sponsor, or are owned by the sponsor.  It may also be shared with:

• Governmental entities that have the right to see or review your health information, such as the Office of Human Research Protections, Department of Health and Human Services (DHHS) agencies and the Food and Drug Administration

• Governmental agencies in other countries

• Doctors and staff at other places that are participating in this study

• The pharmaceutical sponsor, Cephalon, Inc.

• The sponsor of this study and people that the sponsor may contract with for this study.  The name of the sponsor is CTEP/NCI.

• The Data Safety Monitoring Board

• An outside institutional review board

• NABTT CNS Consortium

• Institutional Review Board

 Why will this information be used and/or given to others?

The information will be used to see if you are eligible to enroll in the study.  It will be shared with the parties above so these parties can monitor the research.

 What if I decide not to give permission to use and give out my health information?

If you refuse to give permission, you will not be able to be in this study.

 May I withdraw or revoke (cancel) my permission?

Yes, but this permission will not stop automatically.  You may withdraw or take away your permission to use and disclose your health information at any time.  You do this by sending written notice to the study doctor. 

 Is my health information protected after it has been given to others?

If you give permission to give your identifiable health information to a person or business, the information may no longer be protected.  There is a risk that your information will be released to others without your permission.

 WHAT ARE MY RIGHTS AS A PARTICIPANT?

 Taking part in this study is voluntary.  You do not have to choose to take part.  If you decide to join this research study, you may withdraw from it 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.

 WHO DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?

 For questions about the study or a research-related injury, contact the researcher __________________ (NAME{S}) at  __________________ (TELEPHONE NUMBER).

 For questions about your rights as a research participant, contact the__________________ (NAME OF CENTER) Institutional Review Board (which is a group of people who review the research to protect your rights) at __________________ (TELEPHONE NUMBER).

 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.

 You will get a copy of this form. You may also request a copy of the protocol (full study plan).

 SIGNATURE

        I agree to take part in this study. 

        Participant ________________________________

       Date _____________________

 Investigator ________________________________

 Date _____________________

 Witness  ___________________________________

 Date  ____________________

Phase I Consent

Phase I/II, Open-Label, Non-Randomized, Multicenter, Single Agent Study of Intravenous SDX-102 for the Treatment of Patients with MTAP-Deficient High Grade Recurrent Malignant Glioma

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) that has grown or has recurred.

WHY IS THIS STUDY BEING DONE?

The purpose of this study is to find the highest dose of SDX-102 that can be given without causing severe side effects. This research is being done because currently, there is no effective treatment for this type of cancer. SDX-102 is an investigational drug. SDX-102 may be active in many types of cancer. We are studying the proper dose of SDX-102 to give to patients with brain tumors. This means we will give increasing doses of SDX-102 until patients have major side effects. Your dose will not be increased. You will be given the same or lower dose throughout your treatment. We will also be looking at the side effects of SDX-102.

HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?

Approximately 6-18 people will take part in the study

WHAT IS INVOLVED IN THE STUDY?

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

Only patients whose tumors are found to have MTAP deletion can be considered for this study.  Your tumor has already been tested and found to have MTAP deletion.  If you take part in this study you will have the following tests and procedures:

You will have a physical and neurological examination, an electrocardiogram, and a chest x-ray. You will also have an MRI or CT scan of the brain. Your blood and urine will also be tested. SDX-102 will be given into a vein over five days. If you experience nausea or vomiting during or after your treatment you will receive additional medications to lessen this. Some patients experience headache or constipation as a side effect of the anti-nausea medicine. You will receive a SDX-102 infusion continuously for five days in a row. Each week of treatment will be followed by 2 weeks with no treatment. This 3 week period is called a cycle. Another brain scan will be performed after three cycles of chemotherapy (9 weeks). The brain scans (MRI or CT) would be part of routine cancer care.

On Day 1, SDX-102 continuous intravenous (IV) infusion will begin and will continue without stopping for 5 days through a central venous access device or central line. A central line is a broad term that includes many types of catheters (thin, flexible, hollow tubes) that are inserted into and positioned within a large vein that is near the heart. Generally this procedure is done under local anesthesia as an outpatient prior to starting treatment. This is a temporary device that will remain in place as long as your doctor thinks it is appropriate for your treatment. You will also carry a small battery-powered pump while receiving the SDX-102 treatment. The pump is connected to a bag that contains the SDX-102 study drug. The pump slowly delivers the SDX-102 into the central line. You will need to return to the study site on day 6 to have your infusion discontinued. During the five-day infusion, the study doctor or a study staff member will call you on or about day 3 to ask you how you are feeling or ask you to return to clinic for evaluation, if necessary.

As part of this study, we will be collecting extra blood samples to check the amount of chemotherapy in your blood. During the first cycle of therapy, on Day 1 and Day 6, you will be asked to remain in the clinic area for up to 8 hours to allow for blood sampling to check the amount of chemotherapy in your blood.  On each of these days 7 samples of blood will be taken.  Each sample taken will equal about a teaspoon of blood.  These tests are for research purposes. They would not be done if you were not on a clinical trial. If at any point your dose needs to be reduced, additional blood samples will be taken. This would occur on Day 1 and Day 6 of the new dose. The schedule of blood samples taken will be the same as your first cycle.

HOW LONG WILL I BE IN THE STUDY?

All cancer treatments carry some risk of side effects and discomfort. 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. When possible, other drugs will be given to make the side effects less serious and uncomfortable.

Many side effects go away shortly after the SDX-102 is stopped, but in some cases side effects can be serious, long lasting, permanent, fatal.

Likely side effects: It is likely that SDX-102 will cause ulcers, redness and pain in your mouth. SDX102 may cause a decrease in the number of white cells and platelets in your blood. A decrease in white blood cells means that you have a higher risk of getting an infection. A decrease in platelets means you have an increased risk of bleeding.

Other side effects: SDX-102 may also cause headache, diarrhea, nausea, vomiting, low blood pressure, high blood pressure, rash, kidney and liver problems, leg cramps, fatigue and a lack of motivation, sleepiness, confusion and disorientation.

Other Risks: The collection of your blood may cause pain, swelling bruising or infection at the site of the needle puncture.

Financial risks: There may be extra costs with this treatment. Some of the costs of other medications, equipment, blood tests and brain scans or hospitalization,may not be covered by your insurance company. We encourage you to work closely with your insurance company to find out exactly what is covered for this research study.

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 and for four weeks after your last treatment on this study. You should not nurse a baby while on this study. Ask about counseling and more information about preventing pregnancy. SDX-102 can affect your menstrual cycles and your ability to have children in the future.

For more information about risks and side effects, ask the researcher or contact

ARE THERE BENEFITS TO TAKING PART IN THE STUDY?

If you agree to take part in this study, there may or may not be direct medical benefit to you. We do not know if SDX-102 will be better or worse than other treatments for this tumor. We hope the information learned from this study will benefit other patients with brain tumors in the future.

You do not have to join this clinical trial to get treatment for your brain tumor. Instead of being in this study, you have these options. You might be able to have further surgery, radiation therapy or chemotherapy. You may also be eligible for other research studies. You can also choose to have no therapy at this time with care to help you feel more comfortable. Please talk to your doctor about these and other options.

This section tells you what information about you may be used and given out in this study and who may give and receive the information. By signing this consent form, you agree that health information that identifies you may be used and/or given out as needed in this study. _________________ has a policy to protect health information that may identify you. Federal and state laws also protect your privacy. ______________________ has procedures in place to support these policies and laws.

Information that identifies you and relates to your health or medical condition may be used or given out in this study. Information that identifies you can include your name, address, telephone number, date of birth, Social Security number and other details about you. Information that relates to your health or medical condition includes:

Information obtained from the activities and procedures outlined in this consent form, which may include:

i) things done to see if you can join this study, such as physical examinations, blood and urine tests and any other information that you share with us, including information about your health history and your family health history; and

ii) information obtained during the study, such as how you respond to the study activities or procedures, information we learn in study visits, phone calls, surveys, physical examinations, blood and urine tests, x-rays and other tests and any other medical information we learn from you as a participant in this study.

Some people may see your health information and may give out your health information during this study. These include the researcher and the research staff, the institutional review boards and their staff, legal counsel, audit and compliance staff, officers of the organization and other people who need to see the information to help this study or make sure it is being done as it should.

Other organizations may see your health information during this study. These include:

• 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 pharmaceutical sponsor, Cephalon, Inc.
• The sponsor of this study and people that the sponsor my contract with for this study. The name of the sponsor is CTEP/NCI.
• The Contract Research Organization. The name of the CRO is Theradex.
• The Data Safety Monitoring Board
• An outside institutional review board
• NABTT CNS Consortium

Your information will be used and given out to carry out this study and to evaluate the results of this study.

You do not have to give your permission to use or give out your health information. However, if you do not give permission, you may not participate in this study.

You may cancel your agreement to allow your health information to be used or given out at any time by sending a written notice to the Institutional Review Board Office, __________________________________. If you do this, you are leaving this study. If you leave this study, no new health information about you will be gathered after that date. However, information gathered before that date may be used or given out if it is needed for this study or any follow-up for this study.

If your health information is given to someone not covered by these policies and laws, that information may no longer be protected, and may be used or given out without your permission.

This authorization to use and give out health information continues until the end of this study and any necessary data analysis follow-up activities for this study.

Research studies involving human volunteers are reviewed by an Institutional Review Board (IRB). The IRB is made up of doctors, nurses, scientists, non-scientists and people from the community. The IRB is responsible for protecting participant’s rights.

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

Salmedix will provide you with the investigational agent and the pump to administer it 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.

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

Taking part in this study is voluntary. You do not have to choose to take part. If you decide to join this research study, you may withdraw from it 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.

For questions about the study or a research-related injury, contact the researcher __________________ (NAME{S}) at __________________ (TELEPHONE NUMBER).

For questions about your rights as a research participant, contact the__________________ (NAME OF CENTER) Institutional Review Board (which is a group of people who review the research to protect your rights) at __________________ (TELEPHONE NUMBER).

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.