MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC): Phase I, first-in-human study in patients (pts) with advanced gastrointestinal (GI) malignancies expressing GCC.

TPS3646 Background: MLN0264, an investigational ADC that targets GCC, consists of a fully human monoclonal antibody conjugated to the cytotoxic microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. MMAE and the linker technology are licensed from Seattle Genetics. GCC is a cell surface protein expressed by normal intestinal epithelial cells, ~95% of metastatic colorectal cancer (mCRC), and subsets of gastric and pancreatic cancers. In normal tissue, GCC is expressed on the apical side of epithelial cell tight junctions; therefore, systemically delivered GCC-targeting agents are expected to be preferentially delivered to tumor tissue in which cell polarity is disrupted. MLN0264 has demonstrated antitumor activity in mouse xenograft models of GCC-expressing tumors (Veiby et al. EORTC-NCI-AACR, 2012), supporting the scientific rationale for this first-in-human study. Methods: This study (NCT01577758) was designed to evaluate MLN0264 in ~60 adult pts with GI malignancies expressing GCC (≥1+), measurable disease by RECIST, and ECOG PS 0/1. This study is being conducted at 4 centers in the US and EU and is estimated to last ~36–42 months. Pts receive IV MLN0264 on day 1 of 21-day cycles for up to 17 cycles or until disease progression/unacceptable MLN0264-related toxicity. Dose escalation is proceeding via an adaptive Bayesian continual reassessment model approach based on dose-limiting toxicities in cycle 1. Following determination of the maximum tolerated dose (MTD), up to 14 pts each will be enrolled to mCRC and gastric carcinoma expansion groups to further characterize the safety, tolerability, and pharmacokinetics (PK) of MLN0264 and evaluate its clinical activity. The primary objectives are to evaluate the safety and tolerability, determine the MTD, and describe the PK of IV MLN0264. Secondary objectives are to evaluate the antitumor activity and immunogenicity of MLN0264. An exploratory objective is to examine the relationship between levels of GCC protein expression in tumor tissue and clinical response. Enrollment as of Jan 2013 was 12 pts. Clinical trial information: NCT01577758.