Phase 1b Study of AdV-tk + Valacyclovir Combined With Radiation Therapy for Malignant Gliomas

This study was designed to include patients with newly diagnosed unresectable (Arm A) and
resectable (Arm B) malignant glioma. Three dose levels of AdV-tk were evaluated with a fixed
dose level of valacyclovir prodrug. AdV-tk was delivered to tumor cells by stereotactic
injection into the tumor at the time of biopsy (Arm A) or injection into the tumor bed
following resection (Arm B). Oral valacyclovir began 1-3 days after the AdV-tk injection and
continued for 14 days. Standard radiation therapy began 3-7 days following the AdV-tk
injection to maximize synergy with radiation. Standard temozolomide could be administered
after completion of valacyclovir.

Inclusion Criteria:

- Presumed malignant glioma based on clinical and radiologic evaluation (pathologic
confirmation of malignant glioma must be made at the time of stereotactic biopsy or
resection prior to AdV-tk injection; if this is not possible, the injection will not
be performed and the subject will no longer be eligible for the study).

- Tumor must be accessible for injection and must not be located in the brainstem,
midbrain, contained within the ventricular system, or located in an infratentorial
location.

- Patients must be planning to undergo standard radiation therapy.

- Patients must be 18 years of age or older.

- Performance status must be KPS > or equal to 70.

- Patients must have SGOT (AST) < 3x upper limit of normal.

- Patients must have serum creatinine < 2mg/dl and calculated creatinine clearance
>10ml/min.

- Patients must have platelets > 100,000/mm3 and WBC > 3000/mm3.

- Patients of reproductive age must agree to use a medically accepted form of birth
control while on the study.

- Patients must give study specific informed consent prior to enrollment.

- Patients must be able to tolerate MRI scan procedure

Exclusion Criteria:

- Prior or ongoing liver disease including known cirrhosis, hepatitis B or C infection
but not to exclude patients with a distant history of resolved hepatitis A infection.

- Patients on immunosuppressive drugs (with exception of corticosteroid)

- Known HIV+ patients.

- Patients with acute infections (viral, bacterial or fungal infections requiring
therapy).

- Pregnant or breast feeding patients. Female patients of childbearing age must have
negative serum or urine pregnancy test within 1 week of beginning therapy.

- Evidence of metastatic disease or other malignancy (except squamous or basal cell
skin cancers).

- Prior radiation therapy to the brain or prior treatment for brain tumor (except prior
biopsy or subtotal resection).

- Other serious co-morbid illness or compromised organ function.

- Patients may not receive temozolomide until valacyclovir completed and may not
receive other investigational anti-tumor agents within 30 days prior to study entry
or during active participation in the study (defined as from study entry until tumor
progression).