HSV-tk and XRT and Chemotherapy for Newly Diagnosed GBM

This is a prospective, phase I-II study to assess the efficacy and toxicity of HSV-tk +
valacyclovir gene therapy in combination with radiotherapy and standard of care chemotherapy
for anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM). This study is comprised of
newly diagnosed patients with AA or GBM.

Clinical response will be evaluated by neurological evaluation, neuropsychological testing,
and imaging studies as well as by histological examination. Blood samples will be taken for
systemic immunological response, blood counts, and liver functions tests. Genetic testing of
tumor tissue will be performed, including genetic analysis and cell cultures. Toxicity will
be graded by the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and Radiation
Therapy Oncology Group (RTOG) neuro-toxicity scores (see Appendices). Patients will also be
followed to assess median time to progression and median survival.

Inclusion Criteria:

- All patients must have frozen section biopsy proven anaplastic astrocytoma or
glioblastoma multiforme without evidence of multifocal tumor or leptomeningeal
metastatic disease or brainstem involvement as well as radiographic evidence
consistent with these diagnoses.

- Life expectancy ≥ 12 weeks.

- Patients should have the following characteristics: newly diagnosed anaplastic
astrocytoma or glioblastoma demonstrated by frozen section biopsy, ECOG performance
status of 0-1. No evidence of other active malignancy (except squamous or basal cell
skin cancers).

- Signed informed consent to participate in the study must be obtained from patients
after they have been fully informed of the nature and potential risks of the study by
the investigator (or his/her designee) with the aid of written information.

- Willing to provide biopsies as required by the study.

- WOCBP must have a negative serum pregnancy test within 7 days prior to the
administration of the first study treatment. Women must not be lactating.

- WOCBP and men must practice an effective method of birth control

- Patients must have adequate baseline organ function as assessed by the following
laboratory values before initiating the protocol:

- serum creatinine < 1.5 mg/dL

- T. bilirubin < 2.5 mg/dL, ALT, AST, GGT and Alk Phos < 2 x normal

- Platelet count > 100,000/ml , ANC> 1500/ml , Hgb> 10 gm/dL

- Normal partial thromboplastin time (PTT) and Pro-Thrombin Time (PT)

Exclusion Criteria:

- Prior treatment with immunomodulatory therapy, immunotherapy, and/or gene vector
therapy in the past 3 months.

- Any cytotoxic chemotherapy, RT, or immunotherapy or any investigational drug within 3
weeks of study treatment start.

- Evidence of multifocal disease, brainstem involvement, or leptomeningeal metastasis,
Discrete areas of contrast enhancement connected by abnormal T2 FLAIR signal on MRI
scan are not considered multifocal disease, as this represents a single tumor.

- Patients on immunosuppressive drugs (other than steroids for brain edema).

- Liver disease, such as cirrhosis or active/chronic hepatitis B or C.

- History of or current alcohol misuse/abuse within the past 12 months.

- Known or suspected allergy or hypersensitivity to any component of the proposed
regimen (gene vector/Valacyclovir).

- Inability to swallow food or any condition of the upper gastrointestinal tract that
precludes administration of oral medications (Valacyclovir).

- No active malignancy except for non-melanoma skin cancer or in situ cervical cancer or
treated cancer from which the patient has been continuously disease free for more than
3 years.

- The presence of active CNS toxoplasmosis infection or Progressive Multifocal
Leukoencephalopathy demonstrated on CT or MRI imaging

- The presence of active untreated cellulitis or untreated wound infections. Treated and
resolving cellulitis and infections are not an exclusion criteria.

- Active IV drug abuse or severe opioid abuse

- Pregnant or breastfeeding women or women/men able to conceive and unwilling to
practice an effective method of birth control. WOCBP must have a negative serum
pregnancy test within 7 days prior to the administration of the first study treatment.

- Presence of active or suspected acute or chronic uncontrolled infection or history of
immunocompromise, including a positive HIV test result.

- Patients < 18 years of age

- Unwilling or unable to comply with the study protocol.