HSV-tk + Valacyclovir + SBRT + Chemotherapy for Recurrent 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 in recurrent glioblastoma
multiforme or anaplastic astrocytoma. This study is comprised of patients who have failed
standard of care treatment (maximal safe resection followed by chemoradiation).

Clinical response will be evaluated by neurological evaluation, neuropsychological testing,
and imaging studies as well as by histological examination wherever a re-operation is
clinically indicated. Blood samples will be taken for systemic immunological response, blood
counts and liver functions tests. Toxicity will be graded by the Common Terminology Criteria
for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG) neuro-toxicity scores.
Patients will also be followed to assess median time to progression and median survival.

Inclusion Criteria:

- All patients must have biopsy proven recurrent anaplasatic astrocytoma or glioblastoma
multiforme without evidence of multifocal tumor or leptomeningeal metastatic disease
or brainstem involvement. Multifocal disease does not exist if enhancing areas are
connected by abnormal T2 FLAIR on the MRI scan.

- Radiographic evidence of recurrence/progression by iRANO criteria

- ≥ 3 weeks since any major surgery, completion of RT, or completion of all prior
systemic anticancer therapy (adequately recovered from the acute toxicities of any
prior therapy).

- Life expectancy ≥ 12 weeks.

- Patients should have the following characteristics: recurrent glioblastoma or AA
demonstrated by biopsy or imaging study, ECOG performance status of 0-1, has had prior
surgery and radiotherapy /chemotherapy for the glioblastoma.

- 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 AP < 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)

- Non English speaking patients can participate in this study

Exclusion Criteria

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

- Prior treatment with the HSV-tk vector used in this study

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

- Evidence of multifocal disease, brainstem involvement, or leptomeningeal metastasis

- 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-HSV-tk, 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
5 years.

- 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.

- 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