A first-in-human phase I study of MORAb-004 (M4), a humanized monoclonal antibody recognizing endosialin (TEM-1), in patients with solid tumors.

Abstract

3016 Background: Endosialin (TEM-1) is a membrane glycoprotein on the cell surface of activated mesenchymal cells (e.g. pericytes, fibroblasts and mesenchymal tumor cells) and on a subset of human cancers. It is involved in the development of tumor vasculature, stromal/tumor organization and PDGFRb signaling. M4 is a humanized IgG monoclonal antibody which targets TEM-1. Preclinical studies suggest that M4 may have single agent activity via inhibition of the tumor microenvironment and by direct effects on tumors expressing this target. Methods: A phase I dose escalation study in patients (pts) with advanced solid tumors was conducted to evaluate the safety, pharmacokinetic profile and preliminary efficacy of M4 administered intravenously on a weekly schedule; final results are presented. Results: 36 pts refractory to therapy were treated at 10 dose levels (0.0625 to 16 mg/kg administered i.v. on a weekly schedule). Drug-related adverse events (AE) observed were primarily infusion toxicity (grade 1 and 2 fever, chills, headache, myalgia). The MTD was determined to be 12 mg/kg. DLT of grade 3 vomiting was observed at 16 mg/kg. Preliminary pharmacokinetic (PK) analyses demonstrate M4 accumulation beginning at 4 mg/kg, and that elimination mechanisms are saturable beginning at 0.25 mg/kg. Exposure (AUC) increases in a greater than dose-proportional manner, with the apparent t1/2 increasing proportionally with dose. Tumor shrinkage (Minor/mixed tumor responses, mR) were seen in four pts (soft tissue sarcoma (2), hepatocellular carcinoma, pancreatic neuroendocrine tumor). Each mR was associated with prolonged disease stabilization in these pts (6-14 months). A cohort (n=4) of pts with refractory colorectal carcinoma demonstrated disease stabilization (15-24 weeks). Analysis of archival tumor revealed TEM-1 stromal staining in all cases with tumor cell expression noted on a subset of tumors of mesenchymal origin. Conclusions: In this phase I study, M4 was tolerated up to 12 mg/kg (MTD) and early signs of potential activity were observed. Expanded cohorts of 1-12 mg/kg are ongoing to further define an optimal dose.