A phase I dose escalation study of weekly BI 836845, a fully human, affinity-optineized, insulin -like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers

[[abstract]]Background: The IGF signaling pathway has an important role in neoplasia and is associated with cancer progression, prognosis, and resistance to anti-cancer treatment. IGF-1 and IGF-2 are up-regulated in many tumors and exert multiple cellular activities through endocrine, autocrine, and/or paracrine manner. BI 836845 binds to and neutralizes the function of IGF-1 and IGF-2. The ligand-targeting approach differs from receptor-targeting by additional inhibition of IGF-2 signaling through IR-A. Objectives of this first-in-human trial were to assess the MTD or relevant biological dose (RBD), safety, PK, pharmacodynamics, and anti-tumor activity of weekly BI 836845 in cancer patients. Methods: In a 3+3 design, sequential cohorts of 3 to 6 patients (pts) with advanced or metastatic solid cancers refractory or not amenable to standard therapy received a weekly 1-hour intravenous infusion of BI 836845 following an AE-guided dose escalation. Treatment was continued in the absence of progressive disease and undue AE. The primary endpoints were DLT, MTD and/or RBD. Results: 48 pts, median age 57.5 (19-76) years were treated with BI 836845 at 14 dose levels (range: 10 to 1800 mg). Only one DLT, potentially drug-related grade 3 pulmonary hemorrhage originating from a tumor-adjacent vessel, was observed at 450 mg. The other of the two reported grade 3 drug-related AEs was lymphocyte decrease. No drug-related grade 4 or 5 AE was reported. Infusion-related reaction or drug-related hyperglycemia was not reported. MTD was not reached. BI 836845 showed a dose-proportional PK with a terminal half-life of about 6 days, a volume of distribution of 5.8 L, and a total plasma clearance of 0.5 mL/min. A RBD for further clinical development was selected at 1000 mg weekly. There were two confirmed PRs (nasopharyngeal carcinoma, at 800 mg; peripheral primitive neuroectodermal tumor, at 1050 mg) and 12 pts (25%) with confirmed SD. Conclusions: Weekly infusion of BI 836845 is well tolerated in cancer patients in the dose range tested without determination of a MTD. Preliminary anti-tumor activity has been observed