cotara

An Open-label, Dose Confirmation and Dosimetry Study of Interstitial ¹³¹I-chTNT-1/B MAb (COTARA™) For the Treatment of Glioblastoma Multiforme (GBM) at 1^st or 2^nd Relapse

2. Patients much have a histologically proven glioblastoma multiforme, focal disease, which is progressive or recurrent following treatment (radiation, chemotherapy)

(Patients with previous low grade astrocytoma who progressed after treatment (radiation therapy, chemotherapy and are found to have glioblastoma multiforme are

5. Patients must be maintained on a stable corticosteroid regimen (± 4 mg) for at least two weeks prior to study entry.

6. Within 2 weeks prior to starting treatment, patients must have normal hematologic, and renal functions (Absolute neutrophil count ³1500/mm³, platelets ³100,000/mm³, hemoglobin ≥ 9.0g/dL, creatinine £ 1.7mg/dl, serum bilirubin ≤ 1.5 mg/dL, BUN within 2 times the upper limit of normal and Transaminases ≤ 2.5 times above the upper limits of the institutional norm).

7. 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. An interval of at least 4 weeks must have elapsed from time of surgery.

8. Patients must have signed an Institutional Review Board (IRB) approved informed consent form prior to registration on study.

1. Patients with infratentorial tumor(s), tumor(s) that communicate with the ventricles or intraventricular disease.

3. Patients with diffuse disease (i.e., any satellite lesion > 1.5 cm from the anticipated location of any catheter tip or > two satellite lesions).

4. Patients with medical illnesses which would preclude protocol treatment (e.g., serious concurrent infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac dysrhythmia.)

6. Patients with a concurrent malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients with a prior malignancy are ineligible unless they have been free of disease for ³ five years.

7. Patients who have received local therapy such as any of the following will be ineligible:

§ Other local therapy such as immunotherapy, or therapy with biologic agents including immunotoxins, immunoconjugates, antiangiogenesis compounds, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK, or gene therapy)

8. Patients with psychological or sociological conditions, addictive disorders or other conditions, which would in the investigator’s judgment preclude compliance with the study protocol.

9. Patients with ventricular invasion outside the anticipated radiation treatment volume.

11. Patients who have had a surgical resection within 4 weeks prior to baseline.

12. Patients who have received investigational agents within 30 days prior to baseline.

13. Patients who have previously received treatment with any monoclonal antibody.

17. Patients who are pregnant or breast-feeding. All patients with the potential for pregnancy should be counseled and requested to follow acceptable birth control methods to avoid conception. The activity of this drug may be harmful to the developing fetus or nursing infant.

Cohorts of 3 patients each will be treated. Dose escalation may proceed after all patients in the previous dose cohort have been observed for 6 weeks and all treatment-related toxicities have returned to ≤ Grade 2. The 6 week evaluation period for determining toxicity will begin at the time the therapeutic dose is given. The dose levels and dose escalation schema are presented in Tables 1 and 2 below.

Cohort	Dose Level in mCi/cc of Gross Tumor Volume (GTV)
1	1.5 (Starting dose)
2	2.0
3	2.5 (Maximum dose)

Adverse events and concomitant medications will be collected for at least 90 days after the therapeutic dose administration. Patients will be evaluated for clinical and laboratory assessments weekly for 4 weeks after drug infusion, then every 2 weeks for 4 weeks, then every 4 weeks until disease progression. In addition, an MRI scan, TSH and HACA determination will be performed every 8 weeks until disease progression. All patients will be followed every 2 months for survival.

Once the MTD has been established ten additional patients will be treated at the MTD.

The first 12 patients accrued to this study will receive a 3 mCi imaging dose of ¹³¹I‑chTNT-1/B MAb 2-4 weeks prior to therapeutic dosing to assess biodistribution and calculate radiation doses (See Appendix 1). Radiation dose estimates will be calculated based on biodistribution data acquired by four methods of acquisitions: a) serial conjugate view imaging b) serial blood collections, c) total urine collection and d) total body retention surveys using a G-M counter at time intervals as specified in Section 9.0 and in accordance with the principles set forth in MIRD Pamphlet No. 16.[i] In addition, a specialized quantitative pinhole collimation technique will be used to characterize thyroid uptake[ii] and SPECT imaging will be performed at 3-7 days post infusion as outlined in Appendix 1. Whole body/organ dosimetry data, including whole body images for all the dosimetry time points, will be submitted to the FDA.

An Open-label, Dose Confirmation and Dosimetry Study of Interstitial ¹³¹I-chTNT-1/B MAb (COTARAÔ) For the Treatment of Glioblastoma Multiforme (GBM) at 1^st or 2^nd Relapse

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 family and friends.

You are being asked to take part in this study because you have a malignant brain tumor (glioblastoma multiforme) that has come back after being treated with standard therapy. This research is being done because currently, there is no highly effective long-term treatment for this type of cancer. Glioblastoma Multiforme is almost never cured with surgery, radiation, and chemotherapy as they are now usually given.

This research study uses an investigational drug called Cotara. Cotara is a drug that uses antibodies linked to radioactive iodine. Antibodies are proteins that recognize and attach to tumor-specific targets. Once the antibodies are inside the tumor and attach to the targets radioactivity is then delivered to the tumor cells. Since the antibody is designed to attach specifically to tumor tissue, the amount of radiation exposure to other areas of the body is potentially reduced.

The purpose of this study is to determine the highest dose of Cotara that can be safely given to patients with primary brain tumors. This means we will give increasing doses of Cotara until patients have major side effects. Once your dose is assigned, it will not be increased. We will monitor the side effects of Cotara. You will receive a low dose, with less toxicity or you may receive a higher dose with more toxicity. In addition, the distribution of the drug in the body will be studied.

At the screening visit you will have standard medical tests (none of these are experimental) to help the study doctor decide if you are able to take part in this study. Your medical and cancer history will be recorded. In addition, a complete physical exam will be done that includes:

· Vital signs (temperature, breathing rate, weight, pulse rate, and blood pressure)

· MRI scan (this procedure takes about 60 to 90 minutes and requires that a needle be placed into a vein in your arm and a dye injected. The image will allow the study doctor to see your brain tumor and estimate its size).

All patients will have their blood tested for Hepatitis. If blood tests show that you have this disease you may not continue in the study. Because we do not know the effect of the study medication on unborn children, pregnant women will not be eligible for participation in this clinical trial and if you are a woman who is able to have children, your blood will be tested to determine if you are pregnant. The pregnancy test must have a negative result and you must be practicing an acceptable method of birth control to continue in the study.

Cotara is injected directly in your tumor through a small tube called a catheter (tube smaller then a piece of spaghetti). Catheters are surgically placed into the tumor and then removed the next day. For this study you will receive two doses of the Cotara which means you will have the catheters placed and removed at two separate times. The first dose is a very small dose that is only given so that we can determine how the drug is distributed throughout your body. We will determine the distribution of the drug by taking a series of body scans and collecting blood and urine samples. Approximately four weeks after receiving the small imaging dose you will receive a higher dose that we believe may be “therapeutic.” It is the second dose of Cotara we hope will deliver radioactivity to the tumor cells. This is the dose we are also studying to find out what side effects are associated with Cotara. Depending on the time that you are enrolled in the study, the second dose you receive may be one of three possible doses (1.5, 2.0 or 2.5 mCi/cc) of the drug.

Three days prior to receiving the imaging dose of Cotara, you will begin taking 2 prescription medications. The first medication is a saturated solution of potassium iodine (SSKI). You will take 20 drops of the SSKI by mouth 2 times a day. The other medication is L-thyroxine. You will take 1 pill (0.1 mg) by mouth once daily. Both medications will be continued until 10 days after receiving the imaging dose of Cotara. You will be required to keep a diary to document the times and doses taken. These medications are taken to prevent your thyroid gland from absorbing the radioactive iodine.

Within 2 weeks before receiving your second dose, you will be reevaluated to help the study doctor decide if you are still eligible to continue taking part in this study. Several of the same screening procedures that were performed prior to your imaging dose will be repeated. You will resume the same two prescription medications three days prior to the second dose of Cotara and continue taking them until 15 days after treatment with the second dose of Cotara. You will be required to keep a diary to document the times and doses taken. These medications are taken to prevent your thyroid gland from absorbing the radioactive iodine.

The day before each treatment with Cotara, you will be admitted to the hospital for surgery. Your study doctor will perform the surgery required to place 2 catheters (very thin tubes) inside the brain tumor. During the catheter placement, you will be anesthetized and you won’t feel the procedure. A non-experimental procedure called a CT (computed tomography) scan will be done after the surgery. This scan will allow the study doctor to see the position of the catheters in relation to the tumor. Following the surgery you will be placed in a hospital room. The Cotara treatment will begin the day after the catheter placement surgery.

About 12 to 24 hours after your surgery, the experimental treatment with Cotara will begin. The medicine will be delivered to the tumor through the catheters using a special pump. It will take about 25 hours to complete the treatment. After the treatment, the catheters will be removed (this will not require a surgery and can be done in your hospital room). You will stay in the hospital until normal levels of radioactivity are measured (usually about 1 to 2 days after treatment stops). Your vital signs will be closely monitored during this period. In addition, your urine and blood (1.5 tablespoons of blood each time) will be collected at various time intervals.

In order to see how Cotara is distributed throughout your body, the following special procedures will be done only after the imaging dose of Cotara:

· Prior to receiving the imaging dose, an additional whole body CT scan (head, neck, thorax, abdomen and pelvis) will be performed.

· The entire amount of your urine will be collected for different time intervals (from the start of drug infusion to the end of infusion, from the end of infusion to 12 hours post-infusion, 12-24 post-infusion, 24-48 hours post-infusion, 48-72 hours post-infusion, 72-120 hours post-infusion, and 120-168 hours post-infusion) to measure the amount of radioactive iodine in your urine. You will be given special instructions for the collection and return of your urine containers back to the hospital after you are discharged.

· Additionally, blood samples (approximately 1.5 tablespoons of blood each time) will be collected at 9 time points after the end of infusion: Day 2 (5 times), Days 4, 5, 8 or 9, and 10 or 11 or 12 to measure the amount of radioactive iodine in your blood.

· Your blood and urine will be monitored weekly until you receive the second dose.

· Nuclear imaging scans will be taken on Day 2 (twice), Day 4, Day 5 and Day 8 or 9 after receiving your imaging dose to measure the amount of the radioactive iodine in your body. An additional nuclear scan will be taken between Day 5 and Day 9 to measure the amount of the radioactive iodine in your thyroid.

· The amount of radioactivity in close proximity to your body will be measured by a device held around your body on Days 2, 4, 5, 8 or 9 and 10 or 11 or 12.

· A SPECT image will be taken from your body only once sometime between Day 5 and Day 9 to image any uptake of radioactive iodine (if any) in any of your organs.

NOTE: For scheduling reasons, a delay of up to 14 days may occur between the screening visit procedures and the imaging dose treatment.

Procedure/Test	Screening/ Baseline	Day -2	Day 0	Day 1	Day 2	Day 4	Day 5	Day 8 or 9	Day 10, 11 or 12	Weekly Until Therapeutic Dose
Physical Exam	X
Chest X-ray & ECG	X
Vital Signs	X
Karnofsky	X
Pregnancy Test	X
Blood Collection	X				X (5 times)	X	X	X	X	X
Urine Collection	X			X	X	X	X	X
Neurological Exam	X
MRI Scan	X
SSKI & L-thyroxine	X	X	X	X	X	X	X	X	X
Catheter Placement Surgery			X
CT Scan			X
Begin Infusion				X
Complete Infusion / Remove Catheters					X
Whole Body Imaging					X (2 time points)	X	X	X
Thyroid Imaging							X
SPECT Imaging							X