Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features

This is the first study in man of Seneca Valley Virus, a virus which seeks and kills certain tumors in non-human model systems. Subjects in this trial will be patients with advanced cancer displaying certain specified neuroendocrine features, pathologically; they will have exhausted standard methods of treatment for their tumor. The primary purpose of the trial is to determine if the virus may be administered safely. Additional purposes are to learn about the distribution of the virus in the body, the elimination of the virus from the body, the immune response to the virus and whether the virus might have some beneficial effects upon the tumors which the patients have. The first patients will be treated with low amounts of virus and subsequent patients may receive higher amounts. At the end of the trial, it is intended to select a dose for further study.

• Seneca Valley Virus (biological agent) (Drug), also known as SVV-001: Dose escalation (starting at 1 × 10\^7 vp/kg), IV (in the vein) over 1 hour in a single administration

Primary outcomes

• Incidence of dose-limiting toxicity and determination of phase II dose [Within 28 days of treatment administration]

Secondary outcomes

• Number of responses according to RECIST criteria [Baseline; at Week 7, Day 7 following therapy and then confirmation scan at least 4 weeks later, if required; and every 2 months for up to 6 months, if required]
• Limited pharmacokinetics, biodistribution and elimination [Until 2 consecutive negative viral assays]
• Limited evaluation of occurrence of neutralizing antibody [Baseline and at Week 2, Day 1 following therapy]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients must have a histologically confirmed solid tumor (including carcinoid) with neuroendocrine features (i.e., expression of >= 1 of the following 3 markers: synaptophysin, chromogranin A, or CD56) that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
* Patients must show evidence of disease progression in the three months prior to treatment with SVV-001.
* Age >= 18 years. Because no dosing or adverse event data are currently available on the use of SVV-001 in patients <18 years of age, children are excluded from this study. Children may be eligible for future pediatric Phase I single-agent trials.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* Life expectancy >= 24 weeks.
* Adequate bone marrow, hepatic, and renal function as defined below:

  * absolute lymphocyte count >= 1,000/ul
  * absolute neutrophil count >= 1,500/ul
  * platelets >= 100,000/ul
  * AST/ALT <= 2.5 x upper limit of normal (ULN) or <= 5 x ULN if liver metastases present
  * total bilirubin <= 1.5 x upper limit of normal
  * creatinine <= 1.5 x upper limit of normal OR

    * creatinine clearance (calculated) <= 60 mL/min/1.73 m2 for patients with creatinine > 1.5 x upper limit of normal.
* Women must have been surgically sterilized or be post-menopausal.
* Men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for up to 6 months.
* Ability to understand and the willingness to sign a written informed consent document.
* Patients must have oxygen saturation of at least 95% on room air.
* Patients must have measurable disease by RECIST (CT and/or MRI).

Exclusion Criteria:

* Patients with small cell histology.
* Patients who have been hospitalized for emergent conditions requiring inpatient evaluation, treatment or procedure during the 30 days prior to entry on study. In addition, emergent conditions requiring inpatient evaluation, treatment or procedure must have resolved or be medically stable and not severe for 30 days prior to entry on study.
* Use of chemotherapy or radiotherapy within 4 weeks of initiation of SVV-001, or continued > Grade 1 adverse events, excluding alopecia, due to agents administered more than 4 weeks earlier.
* Patients with clinically evident Human Immuno-deficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection.
* Patients with > Grade 1 peripheral neuropathy (CTCAE version 3.0).
* Concurrent use of any other investigational agents.
* Presence of or history of central nervous system metastasis.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pre-menopausal women who have not been surgically sterilized. Although SVV-001 has no affect on the ovaries from a toxicological perspective, SVV-001 RNA is present in the ovaries at 12 weeks in animals that were administered high and medium doses. No pre-clinical reproductive tests have been conducted with SVV-001.

• Results publication: Venkataraman S, Reddy SP, Loo J, Idamakanti N, Hallenbeck PL, Reddy VS. Crystallization and preliminary X-ray diffraction studies of Seneca Valley virus-001, a new member of the Picornaviridae family. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Apr 1;64(Pt 4):293-6. doi: 10.1107/S1744309108006921. Epub 2008 Mar 21. PMID 18391430

• Rudin Charles, MD, PhD, Study chair, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins