Modification of tumor suppressor gene expression and induction of apoptosis in non-small cell lung cancer (NSCLC) with an adenovirus vector expressing wildtype p53 and cisplatin

Protocol: Clinical Protocol for Modification of Tumor Suppressor Gene Expression and Induction of Apoptosis in Non-Small Cell Lung Cancer (NSCLC) with an Adenovirus Vector Expressing Wildtype p53 and Cisplatin. Study Chairman: Jack A. Roth, M.D. Patient Eligibility: Patients must have histologic proof of non-small cell lung cancer. Patients must be either unresectable, unable to receive primary external beam radiation therapy, or have failed primary external beam radiation therapy, or have failed chemotherapy. Patients must have either an endobronchial tumor accessible by the bronchoscope with some clinical evidence of bronchial obstruction, or advanced local-regional cancer which is unresectable. All patients must have a life expectancy of at least 12 weeks and must have a performance status of ≤ 2 (Zubrod scale, Appendix B). A tumor biopsy must show a p53 mutation by single-strand conformation or sequence analysis. Patients will be tested for HIV prior to entry onto the protocol and must be HIV-negative. Patients must have adequate bone marrow function (defined as peripheral absolute granulocyte count of > 2,000/mm³ and platelet count of 100,000/mm³), adequate liver function (bilirubin ≤ 1.5 mg/dl), and adequate renal function (creatinine < 1.5 mg/dl). Treatment Plan: (Include dose adjustment). The study will be done with two arms. It is not know what toxicities if any will be caused by the adenovirus. The first arm of the study will allow assessment of toxicities related only to the vector. Patients will receive one intratumor injection of Ad5CMV-p53. The initial dose will be 10⁶ plaque forming units (PFU). Following completion of the first vector-alone group, a second phase will evaluate Ad5CMV-p53 and cisplatin administered concurrently. Patients in Arm II will receive one course of cisplatin at 80 Mg/M2 on day 1 (which can be given as an outpatient) followed by intratumor injection of Ad5CMV-p53 on day 4. Three patients will be entered at each dose level with 6 patients entered at the maximum tolerated or maximum attainable dose (limitation imposed by production of the adenovirus) for each group. The adenovirus dose will increase in one log₁₀ increments from 10⁶ to 10⁹ and half-log increments from 10⁹ to 10¹¹. Patients entered at a given dose level will not be eligible for dose escalation. The dose of cisplatin will remain constant. Pretreatment and Treatment Evaluation: Patients will have a CBC, platelet count, PT, PTT, SMA-12, electrolytes, and a chest x-ray prior to each course of therapy. Serum will be collected pre- and post-treatment for analysis of antibodies to adenovirus proteins. The endobronchial tumors will be photographed bronchoscopically at the beginning of each course. Tumor measurements are to be recorded before each course for all measurable tumors. Fine needle aspirates or core biopsies will be obtained of accessible local tumor. For endobronchial tumors bronchoscopic tumor and normal bronchial epithelial biopsies will be obtained prior to the beginning of each course. Tissue will be fixed immediately in 4% paraformaldehyde and 0.5% gluteraldehyde at 4°C. This will permit extraction of DNA and RNA and permit in situ hybridization. Biopsies will be analyzed for incorporation of the transduced gene into the host genomic DNA and expression of the transduced gene at the RNA level by standard hybridization techniques following polymerase chain reaction and by in situ hybridization. All patients will be evaluable for response and toxicity following one course of therapy. Miscellaneous Information: Not applicable. Statistical Considerations: Three patients will be entered at each dose level with 6 patients entered at the maximum tolerated or maximum attainable dose (limitations imposed by production of the adenovirus). A maximum of 27 patients will be entered in the intratumor group, respectively for each of the treatment groups (Ad5CMV-p53 alone and Ad5CMV-p53 plus cisplatin). Objectives: 1. To determine the maximum tolerated dose of the wild-type p53 adenovirus vector given with and without cisplatin in patients with refractory non-small cell lung cancer. 2. To determine the qualitative and quantitative toxicity and reversibility of toxicity of this treatment approach. 3. To document observed antitumor activity of this treatment approach.