Intratumoral Gene Mediated Cytotoxic Immunotherapy in Patients With Resectable Non-Small Cell Lung Cancer

The purpose of this open-label, dose escalation clinical trial is to investigate the safety
of GMCI prior to surgery in patients with NSCLC. GMCI involves the use of aglatimagene
besadenovec (AdV-tk) injected into the tumor followed by oral valacyclovir prodrug to kill
tumor cells and stimulate a cancer vaccine effect. Killing tumor cells in an immune
stimulatory environment induces the body's immune system to detect and destroy cancer cells.
GMCI has been well tolerated in previous trials in multiple tumor types with clinical,
pathologic and immune responses.

AdV-tk will be injected intratumorally on day 0 during a standard of care staging procedure.
The prodrug, valacyclovir, will be administered orally at a fixed dose for 14 days following
the AdV-tk injection. Then standard of care surgical resection will be performed about 3
weeks after the AdV-tk injection. Chemotherapy and/or radiation may begin 6-8 weeks after
resection surgery. Choice of chemotherapy depends on the treating oncologist.

Inclusion Criteria:

- Pathologically documented non-small cell carcinoma (cytology or histology) that is
accessible via standard-of-care staging procedures: (1) EBUS or (2) surgical
approaches (eg mediastinoscopy, mediastinotomy or VATS).

- Resectable with negative lymph nodes based on imaging with histologic confirmation at
time of the staging procedure prior to AdV-tk injection

- The tumor must be 4cm or greater in diameter based on imaging

- ECOG Performance status of 0 or 1.

- Granulocyte count (ANC) ≥ 1,000/mm3

- Peripheral lymphocyte count ≥ 500/mm3

- Hemoglobin ≥ 9 g/dl

- Platelets ≥ 100,000/mm3

- Total bilirubin ≤ 1.5 x upper limit of normal

- SGOT (AST) ≤ 3x upper limit of normal

- Serum creatinine < 2mg/dl

- Calculated creatinine clearance > 30ml/min

- Patients must give study specific informed consent prior to enrollment

Exclusion Criteria:

- Radiotherapy and/or treatment with chemotherapeutic, cytotoxic, or immunologic agents
within 4 weeks prior to infusion of the vector.

- Known immunodeficiency such as HIV infection

- Active liver disease, including known cirrhosis or active hepatitis

- Use of systemic corticosteroids (>10 mg prednisone per day or equivalent) or other
systemic immunosuppressive drugs

- Patient is pregnant or breast-feeding. Female patients of childbearing age must have
negative serum or urine pregnancy test within 1 week of beginning therapy. Subjects
must use acceptable means of birth control until 30 days after the vector injection.

- Presence of any other life-threatening illness, such as unstable angina, severe oxygen
dependence, significant chronic obstructive pulmonary disease (COPD), end-stage liver
or renal disease. COPD will be considered significant if disease limits activities of
daily living, results in the inability to walk up 1 flight of stair, or requires home
oxygen.

- Presence of known untreated brain metastases.

- Prior bone marrow transplants (including stem cells) except autologous stem cell
transplant without immunosuppression is NOT considered an exclusion.

- Known sensitivity or allergic reactions to valacyclovir