Safety Study of Adenovirus/PNP Coupled With Fludarabine Phosphate to Treat Solid Tumors

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.

Sex

All

Minimum age

19 Years

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.

• DERIVEDRosenthal EL, Chung TK, Parker WB, Allan PW, Clemons L, Lowman D, Hong J, Hunt FR, Richman J, Conry RM, Mannion K, Carroll WR, Nabell L, Sorscher EJ. Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors. Ann Oncol. 2015 Jul;26(7):1481-7. doi: 10.1093/annonc/mdv196. Epub 2015 Apr 21. PMID 25899782