Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer

Introduction: Patients with recurrent ovarian cancer were treated with a re plication-deficient recombinant adenovirus containing the herpes simplex vi rus thymidine kinase gene administered intraperitoneally (i.p.) followed by administration of an anti-herpetic prodrug and topotecan. Materials and Methods: A total of 10 patients with stage IIIc epithelial ov arian cancer underwent secondary debulking to less than or equal to 0.5 cm residual tumor. Patients with normal i.p. flow received i.p. delivery of ad enovirus. Two patients each were treated on dose level 1 (2 x 10(10) vector particles (VP)), dose level 2 (2 x 10(11) VP), and dose level 3 (2 x 10(12 ) VP); four patients were treated on dose level 4 (2 x 10(13) VP). Acyclovi r and topotecan were started 24 hours after vector delivery. Results: No patient treated at any dose level incurred unanticipated toxic effects, and all side effects resolved. The most common adverse event was m yelosuppression: grade 3 or 4 thrombocytopenia with grade 2-4 anemia in thr ee patients and grade 3 or 4 neutropenia in eight patients. Three patients developed thrombocytosis and three patients had a mild elevation of serum g lutamic pyruvic transaminase/alanine aminotransferase. Temperature elevatio ns that were not associated with detectable infection occurred in two patie nts. Discussion: l.p. delivery of adenoviral vector with concomitant topotecan c hemotherapy was well tolerated without significant lasting toxicities. Side effects were independent of the dose of adenoviral vector.