Abstract B24: Biomarker analysis in the first-in-human phase 1a study for vantictumab (OMP-18R5; anti-Frizzled) demonstrates pharmacodynamic (PD) modulation of the Wnt pathway in patients with advanced solid tumors. (2013)

Abstract Background: The Wnt/β-catenin pathway signals through the Frizzled (Fzd) receptor family and is implicated in many human cancers. Vantictumab is a monoclonal antibody that blocks canonical WNT/β-catenin signaling through binding of five Fzd receptors (1, 2, 5, 7, 8) at a conserved epitope within the extracellular domain. Mouse xenograft studies using minimally-passaged, patient-derived xenografts show that vantictumab impedes tumor growth, promotes differentiation, and reduces cancer stem cell (CSC) frequency in multiple tumor types and synergizes with many chemotherapeutic agents (PNAS 109, 11717). In nonclinical models, vantictumab modulates gene expression in tumor cells associated with stem cell and differentiation pathways and down-regulates Wnt pathway genes in the tumor and stroma. As such, vantictumab is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects on the stroma. We sought to determine the pharmacodynamic (PD) effects of various doses of vantictumab on Wnt signaling and stem cell pathways by examining surrogate tissues and serial tumor biopsies from Phase 1a patients. Methods: PD biomarker analysis of surrogate tissues and tumors was performed in the vantictumab Phase 1a dose escalation study in patients with solid tumors. Samples from sixteen patients enrolled in 4 dose-escalation cohorts with vantictumab administered 0.5 mg/kg weekly (QW), 0.5 mg/kg every other week (QoW), 1 mg/kg QW, and 1 mg/kg every three weeks (Q3W) were analyzed. Hair follicle samples and 3 biopsied tumors were collected at Day 0 and Day 28 or Day 35 after vantictumab administration. Additionally, bone turnover markers including β-C-terminal telopeptide (β-CTX), bone-specific alkaline phosphatase (BSAP), Osteocalcin, and Procollagen Type 1 N-Terminal Propeptide (P1NP) were analyzed. Results: Wnt pathway genes (e.g., AXIN2), and stem cell and differentiation genes (e.g., BMP8B, GFI1) were found to be regulated in hair follicles by vantictumab treatment. In tumors, vantictumab inhibited Wnt target (e.g., AXIN2, TCF4), stem cell and EMT genes (HOXA2, ZEB2) and increased the expression of differentiation genes, including MUC4, MUC5B, and MUC20. These PD effects were observed 1 to 2 weeks after dosing and were evident at the lowest vantictumab Phase 1a dose (0.5 mg/kg QoW). There was dose- and schedule-dependent modulation of bone turnover markers. Conclusions: The PD effects of vantictumab on Wnt target, stem cell and differentiation pathway genes in surrogate tissues and tumor tissues from serial biopsies, as well as on bone turnover markers, were clearly established in this first-in-human study. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B24. Citation Format: David C. Smith, Lee Rosen, Min Wang, Chun Zhang, Lu Xu, Rashmi Chugh, Anthony Tolcher, Jonathan Goldman, Jakob Dupont, Raiiner K. Brachmann, Kyriakos Papadopoulos, Ann M. Kapoun. Biomarker analysis in the first-in-human phase 1a study for vantictumab (OMP-18R5; anti-Frizzled) demonstrates pharmacodynamic (PD) modulation of the Wnt pathway in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B24.