Safety Study of Adenovirus/PNP Coupled With Fludarabine Phosphate to Treat Solid Tumors
Condition: Head and Neck Cancer
MeSH terms: Head and Neck Neoplasms
Intervention: Ad/PNP and fludarabine monophosphate
Intervention description: Subjects in the first 3 cohorts will receive 3x10e11 VP for 3 injections and escalating dose levels of F-araAMP (15, 45, and 75 mg/m2 in each sequential cohort) daily for 3 days. The fourth cohort will receive 3x10e12 for 3 injections and 75 mg/m2 fludarabine daily for 3 days.
Intervention MeSH terms: Fludarabine; Fludarabine phosphate
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 19 Years
Healthy volunteers: No
Keywords: gene therapy; advanced solid tumors; Head and Neck cancer; intratumoral therapy

Summary:

      This study will test whether it is possible to introduce new genetic material into a small
      portion of a tumor and have the product of the new gene not only kill those tumor cells that
      were infected initially, but also the surrounding tumor cells as well with limited or no harm
      to the patient. The desired effects of this approach are achieved by focusing potent
      chemotherapies directly within the tumor itself and, as a result, avoiding injury to the
      remainder of the body. In this study, we will use two components, the first of which is a
      virus, known as an adenovirus, that has been crippled (i.e., it cannot make more of itself)
      and loaded with a bacterial gene called E. coli purine nucleoside phosphorylase (PNP).
      Adenoviruses are considered to be relatively safe vehicles for gene delivery and are
      presently being used in numerous human trials and therapies worldwide, including a head and
      neck cancer therapy approved for use outside the United States. The loaded adenovirus will be
      used to deliver the PNP gene directly into a tumor in patients. This gene is not expected to
      have an effect itself. However, the gene produces PNP inside the tumor and this protein will
      activate the second component of the therapy, a drug called fludarabine phosphate, which is
      approved by the FDA for certain types of blood-cell cancers, but has not been shown to be
      effective against most solid tumors. The proposed therapy gives the patient several infusions
      of fludarabine following the injection of the virus carrying the PNP gene and, as the
      fludarabine enters the tumor, it will be converted by PNP into a second compound,
      fluoroadenine. Numerous studies in mice and rats have shown that fluoroadenine is a very
      potent anti-cancer agent and that it will kill the tumor cells where it is made as well as
      those in the immediately surrounding area.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Biopsy confirmed diagnosis of a solid tumor

          -  Failed or exhausted all standard or approved treatment options that would provide
             substantive palliation

          -  Have at least one measurable primary or metastatic tumor on imaging studies or
             physical exam whose potential reduction could provide relief of symptoms or benefit

          -  Tumor is accessible for direct intratumoral injection

        Exclusion Criteria:

          -  Diagnosis of leukemia

          -  Have previously received any gene therapy products or oncolytic viral therapy

          -  Receiving treatment with allopurinol

          -  Received radiation treatment < 4 wks prior to first injection of Ad/PNP

          -  Received chemotherapy < 4 wks prior to first injection of Ad/PNP

          -  Have signs or symptoms of active infection

          -  Receiving chronic systemic corticosteroids or any chronic immunosuppressive
             medications within 14 days prior to first injection of Ad/PNP. Subjects receiving
             short courses of corticosteroids are considered eligible.