Intrapleural AdV-tk Therapy in Patients With Malignant Pleural Effusion

The goal of this open-label, dose escalation clinical trial is to investigate if the
administration of AdV-tk to patients with MPE followed by valacyclovir and chemotherapy is
safe, can be effectively delivered without disturbing standard therapy, and will have
anti-tumor activity in patients with solid tumors.

The first and second dose levels have been completed, and the study is currently expanded to
enroll more patients to dose level 2 with Celecoxib.

Patients will receive one injection of AdV-tk through a pleural catheter on day 0. The
prodrug, valacyclovir, will be administered orally at a fixed dose for 14 days after each
AdV-tk injection. Celecoxib will be administered starting 3 days before AdV-tk and continuing
for 2 days after AdV-tk administration.

Chemotherapy may begin at any time after completion of valacyclovir. Choice of chemotherapy
depends on the treating oncologist.

Inclusion Criteria:

- Patients must have MPE (defined as positive pleural fluid cytology). Eligible patients
include NSCLC, small cell lung cancer, malignant mesothelioma (MM), breast cancer and
ovarian cancer. Diagnosis must be made prior to AdV-tk injection. For patients with
MM, histologic proof is needed, but positive pleural fluid cytology is not required.

- Patients must have an indication for placement of pleural catheter

- Patients must be 18 years of age or older

- Performance status must be ECOG 0-1

- Acute toxic effects from any prior radiotherapy, chemotherapy, or prior surgical
procedures must have resolved to NCI CTCAE v 4.0 grade ≤ 1

- Baseline pulmonary function tests must be FEV1 ≥1 liter or 40% of predicted value (may
be post-drainage and/or bronchodilator)

- Bilirubin ≤ 1.5 x upper limit of normal (ULN) and ALT, AST and alkaline phosphatase ≤
2 x ULN

- Serum creatinine < 2 mg/dl and calculated creatinine clearance > 30 ml/min

- Hemoglobin ≥ 9 g/dL, ANC > 1000/mm3 and platelets > 100,000/mm3

- Serum albumin level ≥ 2.5 g/dL

- Patients must give study specific informed consent prior to enrollment

Exclusion Criteria:

- Patients may not be on systemic corticosteroids (>10 mg prednisone per day) or other
systemic immunosuppressive drugs

- Patient is not known to be HIV+

- Patient is not pregnant or breast-feeding. Female patients of childbearing age must
have negative serum or urine pregnancy test within 1 week of beginning therapy.

- Patient may not have clinically significant pericardial effusion

- Patient may not have other serious co-morbid illness or compromised organ function

- Patient may not have liver disease including known cirrhosis, active hepatitis or
chronic active hepatitis B

- No prior allergic reaction or hypersensitivity to sulfonamides, celecoxib, aspirin or
other NSAIDs

- No concurrent use of other NSAID or aspirin exceeding 100mg/day during celecoxib
administration. No wash-out period required.