PROCLAIM-CX-2009: A first-in-human trial to evaluate CX-2009 in adults with metastatic or locally advanced unresectable solid tumors

Abstract

Background CX-2009 is a novel recombinant Probody™ drug conjugate (PDC) derived from a humanized monoclonal antibody (mAb) against CD166 and conjugated to N-succinimidyl 4-(2-pyridyldithio) butanoate-N2′-deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (SPDB-DM4, licensed from Immunogen), a potent microtubule inhibitor. PDCs are fully recombinant mAb prodrugs designed to remain inactive until they are cleaved into an active mAb by tumor-associated proteases. This tumor-specific activation allows PDCs to target highly and homogeneously expressed tumor antigens while avoiding binding to these same targets on healthy tissue. An example is CD166 (also referred to as activated leukocyte cell adhesion molecule [ALCAM]), which is highly expressed in multiple cancers but also in healthy tissue. In preclinical studies, CX-2009 exhibited antitumor activity and reduced peripheral binding compared to the corresponding anti-CD166 ADC. Trial design PROCLAIM-CX-2009 (PRObody CLinical Assessment In Man) is an open-label, multicenter, dose-escalation study to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of CX-2009 in 7 selected tumor types with high CD166 expression (breast, lung, prostate, ovarian, endometrial, head and neck, and biliary carcinomas). Part A (n ≤ 50) will initiate with accelerated dose titration, followed by a standard 3 + 3 design to determine the MTD and ending in a modified toxicity probability interval 2-design cohort treated at the MTD to determine the RP2D. Part B of the study will be a dose expansion phase testing CX-2009 administered at the RP2D in the same 7 tumor types (up to 14 patients each, n ≤ 98). Eligibility is based on confirmed refractory metastatic or locally advanced unresectable tumor. Outcome measures include assessment of safety, tolerability, pharmacokinetics, and efficacy based on RECIST 1.1. Exploratory biomarkers will characterize tumor CD166 expression and mitotic markers as well as CX-2009 activation in tumor versus peripheral blood. Clinical trial identification NCT03149549