Abstract B55: Phase I/II study of the tumor-targeting human L19TNF-monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors
Authors: Spitaleri Gianluca , De Pas Tommaso M. , Noberasco Cristina , Giovannoni Leonardo , Menseen Hans D. , Zardi Luciano , Toffalorio Francesca , Catania Chiara , Milani Alessandra , Boselli Sabrina , Neri Dario , de Braud Filippo 
Published: June 2012

Abstract
Background: L19TNF-α is a tumor targeted immunocytokine composed of a single chain variable fragment (scFv) directed against the ED-B domain of fibronectin and the human recombinant cytokine tumor necrosis factor-α. It was created to selectively localize TNF-α to tumor tissues and to minimize systemic toxicity. We evaluated safety, early signs of clinical activity and pharmacokinetic properties of L19TNF-α in patients with refractory solid tumors.
Patients and Methods: Six cohorts of patients with refractory solid tumors were planned to receive escalating doses of L19TNF-α (60 minute-intravenous infusion of 1.3, 2.6, 5.2, 7.8, 10.4, e 13 g/kg) on days 1, 3 and 5 of a 21-days treatment cycle (maximum 6 cycles). Serum samples were taken for pharmacokinetic assessment and the analysis of 5-hydroxyindoleacetic acid (5-HIAA; surrogate marker of vascular disruption) during the first treatment cycle. Immunophenotyping (marker panels: CD71/CD8/CD3/CD4 for T-cell; CD71/CD19/CD3/CD56 for NK/B; CD25/CD122/CD3/CD4 for IL-2 expression on T-cell) on blood mononuclear cells was performed on days 1, 5, and 15 of each cycle for the first consecutive patients. The formation of human antifusion protein antibodies to L19 (HAFA) was analyzed at screening and on day 1 of each cycle. Data on safety and activity were collected.
Results: Eightheen patients with solid tumors were recruited into the trial between January 2008 and September 2009. Patient's median age was 59 years (range 35–74), 8 were male and 9 female. Eight patients had colorectal cancer, 3 cholangiocarcinoma, 2 thymoma, 1 gastric carcinoma, 1 papilla Vater adenocarcinoma, and 1 parotid adenoidocystic carcinoma. A maximum tolerated dose was not yet reached. At the highest dose level achieved so far (10.4 g/kg) severe lumbar pain occurred in one patient during the L19TNF-infusion constituting a DLT. Most common (&gt; 20%) toxicities included G1 Chills (100%), G2 Chills (41%), febricula (47%), G1 fever (70%), G1 asthenia (41%), headache (41%), G1 Nausea (52%), G1 vomiting (52%), G1 constipation (30%), herpes simplex recurrence (30%), G1 pain (58%), G2 pain (30%). Eight of the 18 patients achieved confirmed disease stabilization, lasting for 5 months (range: 1.5 to 8 months). All other patients progressed. Baseline and post-treatment 5′HIAA values were measured in patients of the first two cohorts (6 patients). A significant increase of 5′-HIAA levels on day 1 of the treatment (within 12 hours after end of infusion) as compared to baseline was found in most patients. Immunophenotyping, pharmacokinetic, HAFA and 5′HIAA analyses will be presented at the meeting.
Conclusions: L19TNF- up to a dose of 10.4 g/kg was found safe when intravenously administered to patients with advanced progressive solid tumors in an outpatient setting. The observed toxicity profile was mild and reversible. Encouraging long-lasting disease stabilization was found in a larger fraction of patients, in particular in patients suffering from upper tract gastrointestinal adenocarcinomas.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B55.