CLINICAL PROTOCOL - TREATMENT OF ADVANCED CNS MALIGNANCIES WITH THE RECOMBINANT ADENOVIRUS-H5.010RSVTK - A PHASE-I TRIAL

Primary CNS malignancies are responsible for approximately 12,000 deat hs annually in the United States. There has been little change in the outcome for adults with malignant brain tumors over the past few decad es, despite improvements in surgical techniques and advances in radiat ion therapy. These tumors are uniformly fatal one to two years after d iagnosis. The morbidity and mortality of this disease arise from the e ffects of a locally invasive, non-metastasizing lesion. The patients m ay suffer from seizures, paralysis, incoordination, aphasia, confusion , memory loss, sensory deficits or visual loss, depending on the regio ns of the brain affected. In addition, they usually require large dose s of corticosteroids early and late in their illness, and may experien ce disabling side effects of this treatment, such as edema, proximal m yopathy, diabetes, fungal infections or deep vein thrombosis. Few pati ents in the older age group are able to work after the diagnosis. Most of the patients are incapable of self-care for several months before death. The localized transfer of new genes into cancer cells potential ly permits the expression of proteins with specific biologic functions that may provide a means to alter the biology of tumor growth through a variety of mechanisms including increasing tumor immunogenicity, in ducing the local expression of toxic agents, and sensitization of tumo rs to chemotherapeutic agents. Gene therapy with the transfer of the d rug susceptibility gene Herpes virus thymidine kinase (HSV-TK) has sho wn promise in a number of animal models, including CNS tumors. This st udy will evaluate the use of adenovirus-mediated transfer of the HSV-T K gene into primary human brain tumors followed by systemic treatment with ganciclovir. The goals of this phase I study are to evaluate the overall safety and efficacy of this treatment and to gain insight into the parameters that may limit the general applicability of this appro ach. In this phase I study, patients with recurrent gliomas will recei ve stereotactic-guided injections of the virus into the brain tumor, f ollowed by intravenous ganciclovir for 14 days. Patients eligible to u ndergo a palliative debulking procedure will receive the same treatmen t followed by resection on day 7. At the time of resection a second do se of virus will be administered intra-operatively into the residual, unresectable portion of the tumor, and intravenous ganciclovir will be continued for additional 14 days. Tissue removed at the time of resec tion will be analyzed for evidence of adenovirus infection, thymidine kinase expression and signs of inflammation. The size and metabolic ac tivity of all tumors will be followed by volumetric MRI scans and Posi tron Emission Tomography Scans, respectively. Patients will be enrolle d in groups of three, with each group receiving successively larger do ses of adenovirus. This study will quantify the toxicity of this thera py, and provide evidence as to the duration of transgene expression an d virus induced inflammation.