Safety Study of Modified Vaccinia Virus to Cancer

This is a Phase I, open-label, single dose, dose-escalation trial in subjects with melanoma,
breast cancer, or head and neck squamous cell cancer, liver, colorectal or pancreatic
adenocarinoma. The intratumoral subjects will be stratified into 2 groups. Group A includes
those who have been vaccinated with vaccinia virus. A history of vaccination and a scar at
vaccination site is required. Group B subjects will include those who have not been
vaccinated. It is expected that the toxicity profile will be quite different between those
who have been vaccinated previously with vaccinia virus and therefore subjects will be
stratified separately in this Phase I trial. All subjects who have refractory tumors will
receive treatment at one of five dose levels in a single dose sequential dose-escalating
design. Eligible subjects will receive 1 treatment of vvDD-CDSR. A dose can be divided
between 1-3 lesions. The sum total of the maximal diameters of the lesion(s) to be injected
must be < 10cm.

Once the MTD and/or MFD has been defined in the vaccinated I.T. arm described above,
additional subject may be enrolled at one dose level lower than the MTD/MFD and the I.V.
infusion phase may begin. Patients enrolled in the IV infusion arm will receive a single
administration of vvDD-CDSR at one of three dose levels in a sequential dose-escalating
design.

Inclusion Criteria:

- Greater than 18 years of age

- Histologically-confirmed cancer that has progressed despite standard therapy. They
must have one of the following tumor-types: melanoma, breast cancer, or head and neck
squamous cell cancer, liver, colorectal or pancreatic

- Cancer is not surgically curable

- Karnofsky Performance Status (KPS) of > 70 (See Appendix B)

- Anticipated survival of at least 16 weeks

- If sexually-active, willingness to use condoms for 3 months following study treatment
with vvDD-CDSR

- The ability to understand and willingness to sign a written informed consent

- Able to comply with study procedures and follow-up examinations

- Adequate bone marrow function: WBC > 3,500 and <50,000 cells/mm3, ANC > 1,500
cells/mm3, hemoglobin > 10 g/dL, and platelet count > 150,000 cells/mm3

- Adequate renal function: serum creatinine level ≤ 1.2 x ULN

Exclusion Criteria:

- Pregnant or nursing an infant

- Active viral infection (including HIV, Hepatitis B and C)

- Systemic corticosteroid or other immunosuppressive medication use within 4 weeks of
the treatment

- Clinically significant active infection or uncontrolled medical condition (e.g.,
pulmonary, neurological, cardiovascular, gastrointestinal, genitourinary) considered
high risk for investigational new drug treatment

- Significant immunodeficiency (e.g. due to underlying illness and/ or medication) in
subject or household contacts

- History of eczema requiring systemic therapy

- Unstable cardiac disease which includes but is not limited to: Any of the following
within 6 months prior to study entry: MI, unstable angina, congestive heart failure,
myocarditis, arrhythmias diagnosed and requiring medication, or any
clinically-significant change in cardiac status

- Target tumor(s) adherent to a major vascular structure (e.g. carotid artery)

- Subjects who have received radiation, chemotherapy or other potentially
immunosuppressive therapy in 4 weeks prior to study screening

- Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or
pleural effusions

- Experienced a severe systemic reaction or side-effect as a result of a previous
smallpox vaccination

- Subjects with household contacts who are pregnant or nursing an infant, children < 5
years old, have history of eczema that at some stage has required systemic therapy,
or have a significant immunodeficiency due to underlying illness (e.g. HIV) and/or
medication (e.g. systemic corticosteroids) will be excluded unless alternate living
arrangements can be made during the subject's active dosing period and for three
weeks following the last dose of study medication

- Inability or unwillingness to give informed consent.

- CD4 T cell count < 350 per µL blood