Safety and Dose-Finding Study of TM-601 in Adults With Recurrent Malignant Glioma

A Phase I Dose Escalation Study Evaluating the Safety and Biologically Active Dose of TM-601 Based on Perfusion MRI Imaging Criteria in Patients With Progressive and/or Recurrent Malignant Glioma

The purpose of this study is to evaluate the safety and biologically active dose of TM-601 in adult patients with recurrent malignant glioma.

This Phase I study will evaluate the safety of TM-601 in patients with recurrent malignant glioma who have failed first-line, standard therapy.

Study patients will be assigned to receive treatment in 1 of 6 treatment cohorts. Patients will be assigned to each dose level in groups of 3-6 (depending upon treatment response seen within each cohort), with escalation to the next highest dose dependent upon demonstrated tolerance in the previous dosing group.

Patients will be administered an imaging dose of 131I-TM-601, intravenously, to demonstrate tumor-specific localization prior to study treatment with non-labeled TM-601. Eligible patients demonstrating tumor-specific imaging will be assigned to a treatment cohort and will received non-labeled TM-601 once a week for 3 weeks, followed by clinical follow-up visits and MR imaging.

Data from this study will help determine the IV dose of TM-601 required to produce MR perfusion changes (as well as other biomarker changes) in patients with recurrent malignant glioma. It is not known whether participation in this trial will provide patients with benefit in terms of improved tumor control, although pre-clinical evidence and evidence from other clinical trials with 131I TM-601 suggest that TM-601 is an active agent in malignant glioma.

Inclusion Criteria:

Patients Must:

1. Have histologically proven malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma or glioblastoma multiforme) which is progressive or recurrent after external beam radiation therapy (to at least 50 Gy) ± 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.

2. Be ≥18 years of age.

3. Have a baseline Karnofsky Performance status of ≥60%

4. Have a Mini Mental State Exam score ≥ 19.

5. Have a life expectancy, based on the Investigator's judgment, of >3 months.

6. On screening ECG, have a QTc interval of <450 ms.

7. If taking steroids, be on a dose that is stable for at least 5 days prior to the imaging dose.

8. Have recovered from the toxicity of all previous therapy prior to enrollment. If the patient has undergone recent major surgery, an interval of at least 3 weeks must have elapsed between the surgery and the date of the imaging dose.

9. Have adequate organ and marrow function as defined below:

   hemoglobin >9.0g/dL absolute neutrophil count >1,500 mm3 platelet count >100,000 mm3 prothrombin time <1.5 ULN partial thromboplastin time (PTT) <1.5 ULN total bilirubin < 2.0 mg/dL AST(SGOT)/ALT(SGPT) <5 x institutional ULN creatinine (serum) ≤2.0 mg/dL*

   *If serum creatinine is >2.0 then creatinine clearance must be ≥60 ml/min

10. Have a negative serum and urine pregnancy test within 14 days of study drug administration, if female and of child bearing potential.

11. Agree to use an effective form of contraception to avoid pregnancy, if fertile (applicable to both male and female patients).

12. Agree to refrain from nursing, if female.

13. Have signed and dated written informed consent.

14. Be able to comply with treatment plan, study procedures and follow-up examinations.

Exclusion Criteria:

Patients may NOT:

1. Have a 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. (Examples of medical illnesses are [but not limited to] the following: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.)
2. Have a prior malignancy with less than 5-year disease free interval, except for adequately treated basal cell or squamous cell carcinoma of the skin, or in situ cancer of the cervix.
3. Be pregnant or breast-feeding.
4. Have received radiation treatments ≤ 3 months from time of first study drug administration.
5. Have received any cytotoxic chemotherapy, whether conventional or investigational, ≤ 4 weeks prior to enrollment in this study (6 weeks for mitomycin-C or nitrosoureas).
6. Have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to 131I-TM-601 e.g. iodine or iodine-containing drugs.