Abstract B79: A first-in-human Phase 1 study of anti-cancer stem cell (CSC) agent OMP-54F28 (FZD8-Fc) targeting the WNT pathway in patients with advanced solid tumors. (2013)

Abstract Introduction: OMP-54F28 is a first-in-class recombinant fusion protein of the extracellular domain of the human frizzled (FZD) 8 receptor and a human IgG1 Fc fragment. OMP-54F28 binds Wnt ligands and thereby blocks signaling of the WNT/FZD signaling pathway, a key oncologic pathway in numerous tumor types that is implicated in tumor cell de-differentiation and cancer stem cell (CSC) function. In patient-derived xenograft models, OMP-54F28 inhibits growth of several tumor types (such as pancreatic, ovarian, hepatocellular, colorectal, and breast), reduces CSC frequency, promotes differentiation of tumor cells, and synergizes with chemotherapy. Methods: The objectives of this study are to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of OMP-54F28 as a single agent. A 3+3 design was used, and OMP-54F28 was given intravenously every 3 weeks. Results: 17 patients have been treated in 5 dose-escalation cohorts (0.5, 1, 2.5, 5 and 10 mg/kg). The most common related Grade 1 and 2 adverse events (AEs; &amp;gt;10% of patients) were decreased appetite, fatigue, hypocalcemia, nausea, dysgeusia, increased blood pressure, peripheral edema and vomiting. The only related Grade ≥3 AE was Grade 3 anemia in one patient at the 2.5 mg/kg dose level. OMP-54F28 clearance was dose-dependent, consistent with target-mediated drug disposition, with a half-life of approximately 4 days at 10 mg/kg. Exposure at the current highest dose level approximates the exposure in nonclinical models where optimal efficacy was observed. Two patients demonstrated doubling from baseline of β-C-terminal telopeptide (β-CTX), a marker of increased bone turnover, consistent with PD modulation of the WNT pathway in bone by OMP-54F28. One of these patients received zoledronic acid as per protocol (2nd patient declined), and β-CTX returned to baseline. Additional PD biomarker analyses are ongoing in hair follicles, blood cells and paired tumor biopsies. Best tumor response observed was stable disease in three patients (pancreatic cancer, renal cell carcinoma and desmoid tumor) for approximately 3, 3 and 2+ months, respectively. Conclusions: OMP-54F28 is well tolerated through 10 mg/kg. Dose escalation continues, and updated clinical, PK, and PD data will be presented. Bone biomarker data are consistent with modulation of the WNT pathway, and preliminary evidence of clinical activity has been noted in several patients. Three Phase 1b studies in solid tumor indications are being initiated to study OMP-54F28 in combination with chemotherapy and/or targeted agents. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B79. Citation Format: David C. Smith, Michael Gordon, Wells Messersmith, Rashmi Chugh, David Mendelson, Jakob Dupont, Robert Stagg, Ann M. Kapoun, Lu Xu, Rainer K. Brachmann, Antonio Jimeno. A first-in-human Phase 1 study of anti-cancer stem cell (CSC) agent OMP-54F28 (FZD8-Fc) targeting 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 B79.