Oncolytic Adenovirus-Mediated Gene Therapy for Lung Cancer

Nine subjects (3 cohorts, 3 subjects/cohort) with medically inoperable stage I/IIA (T1a -
T2b) NSCLC with tumors measuring > 2 to ≤ 5 cm will receive a single intratumoral injection
of the oncolytic Ad5-yCD/mutTKSR39rep-ADP adenovirus at one of three dose levels (1 x 1011
vp, 3 x 1011 vp, 1 x 1012 vp). Depending on the location of the target lesion, the adenovirus
will be injected either transbronchially (central tumors) or percutaneously under computed
tomography (CT)-guidance (peripheral tumors). Two days later, subjects will be administered
(orally) a 10 day course of 5-fluorocytosine (5-FC) and valganciclovir (vGCV) prodrug therapy
along with 48 Gy (4 fractions of 12 Gy) of SBRT. Prior to and following the adenovirus
injection, subjects will be administered [18F]-FHBG, a HSV-1 TK substrate, and will undergo
PET imaging to quantify HSV-1 TK gene expression. Toxicity assessments will occur twice a
week for the first 2 weeks and then at scheduled follow-up visits through 60 months. The
primary endpoint is toxicity. Secondary endpoints include 1) tumor (radiological) response,
2) local, regional, and distal tumor control, 3) progression-free and overall survival, and
4) quality of life. Exploratory endpoints include 1) intensity, persistence, and
biodistribution of HSV-1 TK gene expression, and 2) association of select serum biomarkers
with toxicity and tumor response.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of NSCLC.

- Clinical stage I/IIA (T1a - T2b; AJCC Staging 7th edition) with a tumor size > 1 cm to
≤ 6 cm in diameter (long axis) based on the following minimum diagnostic workup:

Note: Subjects may have M0 or MX status (e.g., lung nodules that are being observed). Known
M1 disease is excluded. Subjects may have only one target lesion for SBRT.

- Evaluation at lung multi-disciplinary tumor board with recommendation for SBRT within
12 weeks of registration.

- Whole body positron emission tomography (PET/CT) scan within 12 weeks of registration
using [18F]-FDG with adequate visualization of the primary tumor and draining lymph
node basins in the hilar and mediastinal regions.

Mediastinal lymph node sampling by any technique is allowed but not required. Subjects with
> 1.5 cm mediastinal lymph nodes on CT or abnormal PET (including suspicious but
non-diagnostic uptake) may still be eligible if directed tissue biopsies of abnormally
identified areas are negative for cancer.

- Zubrod Performance Status 0 - 2 with 4 weeks of registration.

- Age ≥ 18.

- Subjects must have adequate baseline organ function, as assessed by the following
laboratory values, within 30 days before initiating the study therapy:

- Adequate renal function with serum creatinine ≤ 1.5 mg/dL or creatinine clearance >50
mL/min/m2.

- Platelet count > 100,000/μL.

- Absolute neutrophil count > 1,000/μL.

- Hemoglobin > 10.0 g/dL.

- Bilirubin > 1.5 mg/dL

- AST/SGOT and ALT/SGPT < 3.0 times upper limit of normal (ULN).

- Negative serum or urine pregnancy test within 72 hours prior to the adenovirus
injection for women of childbearing potential.

- Women of childbearing potential and male participants must agree to use a medically
effective means of birth control throughout and for 60 days beyond the treatment phase
of the study.

- Subjects must possess the ability to give informed consent and express a willingness
to meet all of the expected requirements of the protocol for the duration of the
study.

Exclusion Criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 2 years (e.g., carcinomas in situ of the breast, oral cavity, or
cervix are permissible). Subjects with previous lung cancer are permitted if the
subject is disease-free for a minimum of 2 years or if this is a solitary recurrence
in the lung measuring > 2 cm and ≤ 5 cm after surgery.

- Any known metastatic disease. Subjects may have MX status (e.g., lung nodules that are
being observed).

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields.

- Prior chemotherapy for the study cancer.

- Plans for the subject to receive other local therapy (including standard fractionated
radiotherapy and/or surgery and/or other local ablative therapies) while on this
study, except in the case of disease progression.

- Plans for the subject to receive systemic therapy (including standard chemotherapy or
biologic targeted agents), while on this study, except in the case of disease
progression.

- Acute infection. Acute infection is defined by any viral, bacterial, or fungal
infection that requires specific therapy within 72 hours of initiation of the study
therapy.

- Previous history of liver disease including hepatitis.

- Immunosuppressive therapy including systemic corticosteroids. Use of inhaled and
topical corticosteroids is permitted.

- Impaired immunity or susceptibility to serious viral infections.

- Allergy to any product used in the protocol.

- Serious medical or psychiatric illness or concomitant medication, which, in the
judgment of the principal investigator, might interfere with the subject's ability to
respond to or tolerate the treatment or complete the trial.