During the previous funding period, we defined multiple antitumor activities associated with E1A geneexpression and established an appropriate animal model to evaluate the anti-ovarian cancer activity of an E1Aliposomecomplex. A phase I study using ElA-liposome complex targeting of breast and ovarian cancers wascompleted and reported during the previous funding period (Appendix 1-J. Clin. Oncol. 19:3422-3433, 2001).Based on this experience, we initiated a phase II trial of intraperitoneal single-agent E1A gene therapy inpatients with recurrent ovarian cancer in 2001. Because of the small number of patients who met the eligibilityrequirements, we terminated the phase II trial and initiated a new phase l/ll trial that combines chemotherapywith E1A gene therapy and that has more appropriate eligibility requirements. This phase l/ll trial has beenopened and has begun to accrue patients. In the competitive renewal, we will continue both preclinical studiesand clinical trials to ensure the development of an effective therapeutic approach for ovarian cancer thatutilizes gene therapy. To achieve this goal, we propose the following three Specific Aims:
Specific Aim 1 : Tocomplete the phase l/ll trial of E1A gene therapy combined with chemotherapy. Using a novel trialdesign, we will perform a randomized phase l/ll trial in which one arm receives weekly i.v. paclitaxel (toestablish a concurrent control group for a heterogeneous group of patients) and the other arm receives weeklyi.v. paclitaxel with i.p. liposomal E1A gene therapy at different does levels. This study will define the toxicity,maximum tolerated dose (MTD), clinical response rate, and progression-free survival of weekly paclitaxel plusE1A-pd complex treatment. Biopsies will be obtained to monitor therapy at the cellular level.
Specific Aim2 : To develop an ovarian cancer-specific gene delivery system and expression vector. Two approacheswill be used to improve systemic i.v. targeting of E1A gene therapy to treat ovarian cancer xenografts: 1)development of ovarian cancer-specific promoter elements and 2) conjugation of liposomes with targetingpeptides, folate ligand, and anti folate receptor antibodies.
Specific Aim 3 : To develop an effectivecombination of E1A gene therapy with other agents in a preclinical ovarian cancer model. Usingovarian cancer xenografts, we will test the efficacy and toxicity of E1A gene therapy in combination withcytotoxic drugs used to treat ovarian cancer patients as well as novel biologic agents (TNFa and TRAIL).Preliminary data suggest that these agents may exert synergistic antitumor activity at subtoxic doses. Theclinical data from Aim 1 and preclinical insights from Aims 2 and 3 can be combined in the future to designnovel and potentially even more effective therapeutic strategies.
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