A Phase I Dose Escalation Study of Intratumoral or Intravenous Herpes Simplex Virus-1 Mutant HSV1716 in Patients With Refractory Non-Central Nervous System (Non-CNS) Solid Tumors

Inclusion Criteria:

Inclusion of Women and Minorities: The study is open to all participants regardless of
gender or ethnicity.

Inclusion for intratumoral injection: Subject must have a localized lesion amenable to
HSV1716 administration by needle if superficial; by needle and/or catheter if deep or
pulmonary, via interventional radiology without undue risk. Lesion must meet size criteria
specified in section 4.4.9. Localized is defined as a single lesion; however, more than
one lesion may be acceptable if they are contiguous.

Inclusion for intravenous administration: Subject must have metastatic disease or a
localized lesion not deemed suitable for direct injection.

- Age: Subjects must be greater than or equal to 7 years and less than or equal to 30
years of age at the time of signing consent (study entry);

- Histologic Diagnosis: Subjects must have had histologic verification a non-CNS solid
tumor at original diagnosis. The tumor must be amenable to HSV1716 administration
without undue risk. Disease must be considered refractory to conventional therapy or
for which no conventional therapy exists. There must be no available therapy with
demonstrated clinical benefit for the subject as deemed by the subject's primary
oncologist;

- Metastatic Disease: Subjects who have metastasis to the brain are eligible for this
study; however, no metastatic sites within the brain will be considered for
injection.

- Performance Level: Karnofsky greater than or equal to 50. Subjects who are unable to
walk because of paralysis, but who are up in a wheelchair will be considered
ambulatory for the purpose of assessing the performance score.

- Life Expectancy: Anticipated to be greater than or equal to 8 weeks from time of
study entry;

- Subjects must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study;

- Myelosuppressive chemotherapy: Must not have received within 28 days of entry onto
this study (42 days if prior nitrosourea) accompanied by hematopoietic recovery, or
14 days of stopping non-myelosuppressive therapy as long as hematopoietic
requirements are met;

- Biologic (anti-neoplastic agent): Must not have received within 7 days of entry onto
this study(21 days if prior VEGF-Trap and at least 3 half-lives after last dose of a
monoclonal antibody). For biologic agents that have known adverse events occurring
beyond 7 days after administration, this period must be extended beyond the time
during which adverse events are known to occur;

- No Radiation Therapy greater than or equal to 14 days for local palliative XRT (small
port): greater than or equal to 6 months must have elapsed if prior craniospinal XRT
or if greater than or equal to 50% radiation of pelvis; greater than or equal to 42
days must have elapsed if other substantial bone marrow radiation;

- Immunoablative or myeloablative Stem Cell Transplant (SCT): greater than or equal to
6 months must have elapsed from prior autologous transplant. Subjects must not have
graft versus host disease post autologous transplant;

- Investigational agent: greater than or equal to 28 days must have elapsed from
treatment with a different phase I agent;

- Subjects with seizure disorder may be enrolled if on anticonvulsants and well
controlled.

- At the time of enrollment, specified CNS conditions must be less than or equal to
Grade II toxicity per CTCAE 3.0 criteria;

- All subjects must have adequate blood counts defined as: peripheral absolute
neutrophil count (ANC) greater than or equal to 750/uL, Platelet count greater than
or equal to 100,000/uL (may be a post transfusion value), Hemoglobin greater than or
equal to 9.0 gm/dL (may be a post transfusion value)

- Adequate renal function defined as:Serum creatinine less than or equal to 1.5 x upper
limit of normal (ULN) for age or creatinine clearance or radioisotope GFR greater
than or equal to 70 ml/min/1.73 m2;

- Adequate liver function defined as: Total bilirubin less than or equal to 2.0 x ULN
for age, and SGPT (ALT) less than or equal to 2.5 x ULN for age and albumin greater
than or equal to 2g/dL, GGT < 2.5 x ULN

- Adequate cardiac function as defined by: Shortening fraction >25% by echocardiogram
or ejection fraction above the institutional lower limit of normal by MUGA, No focal
wall motion abnormalities as determined by either of the above studies, EKG without
evidence of ischemia or significant arrythmia

- Adequate coagulation as defined by:PT/INR and PTT <1.5 x ULN for age;

- Infectious Disease: Documented evidence of negative tests for the presence of
Hepatitis B surface antigen, Hepatitis C antibody, HIV1 and HIV2 antibodies within
the three months preceding study entry. Subjects who do not have such evidence must
undergo appropriate testing prior to virus administration;

- Lesion Size: The targeted lesion must be at least 18 mm in each of 3 dimensions as
determined by CT or MRI scans. Lesions not meeting this requirement may be used if
volumetric measurements show it to be greater than or equal to 3mL.

Exclusion Criteria:

- Stem cell transplant: No subjects who have received an allogeneic hematopoietic stem
cell transplant are eligible;

- Pregnancy or Breast-Feeding: There is no available information regarding human fetal
or teratogenic toxicities. Pregnant women are excluded and pregnancy tests must be
obtained in girls who are post-menarchal. Males or females of reproductive potential
may not participate unless they have agreed to use an effective contraceptive method
from the time of study entry to a period of no less than four months post the final
HSV1716 injection. For the same period of time, women who participate in this study
must agree not to breast feed;

- Consent: Unable or unwilling to give voluntary informed consent / assent;

- Leukemia: Subjects with leukemia are not eligible for study participation;

- Infection or any other severe systemic disease or medical or surgical condition
deemed significant by the principal investigator;

- Administration of any unlicensed or investigational agent within 4 weeks of entry to
the study;

- Growth factor(s): No PEG-GCSF within 14 days of virus injection (day 0);

- Anti-HSV antivirals: Subjects whose physicians determine that anti-HSV antiviral
therapy (such as acyclovir, ganciclovir, foscarnet, etc.) cannot be safely
discontinued from 2 days prior to the injection to 28 days following the injection
should not be in the study.

- Subjects who have other conditions which in the opinion of the investigator
contra-indicate the receipt of HSV1716 or indicate subject's inability to follow
protocol requirements.