Phase I safety and pharmacology study of the EpCAM/CD3-bispecific BiTE antibody MT110 in patients with metastatic colorectal, gastric, or lung cancer.

Abstract

2573^ Background: MT110 is a bispecific antibody construct (BiTE) binding to epithelial cell adhesion molecule (EpCAM) expressed on most solid cancers, and to CD3 on T cells. MT110 has shown remarkable antitumor activity in preclinical solid tumor xenograft models. For non-Hodgkin's lymphoma and ALL the CD19-specific BiTE antibody blinatumomab has proven to be highly effective in phase I and II clinical testing. Methods: This phase I study evaluates safety, tolerability, pharmacokinetics, and antitumor activity of MT110 in patients (pts) with advanced solid tumors widely expressing EpCAM. A dose escalation with 3-6 pts per cohort is used to determine maximum tolerated dose (MTD) and dose- limiting toxicities (DLT). Starting dose was 1 μ g/d given by continuous i.v. infusion for at least one 28-day cycle. Results: As of Jan 2010, a total of 23 pts (4 gastric cancer, 16 CRC, 1 SCLC, 2 NSCLC; age ranging from 45 to 85 years, 65% of pts with at least 3 lines of previous chemotherapies) have been treated with MT110 in 6 cohorts up to 24 μ g/d. Overall, MT110 was well tolerated with only few and mild clinical adverse events and pyrexia being the only event reported in more than 2 pts. Liver enzyme elevations caused DLTs in 3 patients at 1, 10, and 24 μ g/d, but were fully reversible. Low-dose MT110 pretreatment partially mitigated the increases in liver enzymes. None of the patients who received a second or subsequent treatment cycles showed an increase in transaminases. As also observed with blinatumomab, MT110 caused a rapid and transient redistribution of peripheral lymphocytes. Mean steady-state serum concentrations of MT110 were dose-dependent reaching up to 1.4 ng/ml at 24 μ g/d. None of the pts developed antibodies against MT110. Disease stabilization according to RECIST was found in 7 of 19 evaluable pts, with a median duration of 91 days (range 56-150 days). Expansion of CD8+ T-cell counts by more than 2-fold over baseline was observed in 5 out of 22 pts. Conclusions: Early signs of biological activity have been observed at clinically well tolerated doses of MT110 in this first-in-human clinical trial. Evaluation of T cell-engaging BiTE antibody MT110 at higher doses is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.