A dose finding pharmacokinetic study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors

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3057 Background: L19-IL2 is a tumor targeting immunocytokine constituted by a single chain Fragment variable format directed against ED-B domain of fibronectin and the human cytokine interleukin-2 (IL-2). It has striking anticancer activity in preclinical models. We evaluated safety, pharmacokinetic profile (PK) and activity of L19-IL2 in advanced cancer patients. Patients and Methods: Five cohorts of patients with recurrent/refractory solid tumors received a dose escalation intravenous infusion of L19-IL2 (5, 10, 15, 22.5 e 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 21 days. Serum samples for PK assessment, immunophenotyping and assays for detection of human antifusion protein antibodies to L19 (HAFA) were collected at screening and on day 1, 3, 5 and 10 of each cycle. Results: Eighteen solid cancer patients were enrolled from 11/05 to 9/06 (6 colorectal and 3 renal cell cancer (RCC) patients, 3 with melanoma, and 1 neuroendocrine tumor, thymic carcinoma, biliary tract carcinoma, breast cancer, peritoneal mesothelioma and parotid gland carcinoma). Median age was 49 years (range 35–69), 14 patients were male and 4 female. All patients were evaluable for safety and activity. The maximum tolerated dose was determined to be 22.5 Mio IU IL-2 equivalent. Drug-related dose-limiting toxicities at 30 Mio IU L19-IL2 were hypotension requiring vaso-pressor support and acute renal failure. Treatment-related deaths did not occur, and all toxicities were reversible. Five patients achieved stable disease (RCC, n=3; biliary tract carcinoma, n=1; peritoneal mesothelioma, n=1). All other patients progressed. Immunophenotyping disclosed IL2-typical transient activation of T-cell subsets. Very preliminary data showed a weak induction of HAFA at day 10 in 5 patients. These data could not be confirmed by competition ELISA experiments. Conclusions: Up to 22.5 Mio IU IL2 equivalent of L19-IL2 can be safely administered to advanced solid cancer patients in an outpatient setting. Some evidence of clinical activity in patients susceptible to immunomodulatory therapy (RCC) was found. All observed toxicity was mild and reversible. An expanded study at recommended dose in RCC patients is currently ongoing. [Table: see text]