Pre-final analysis of first-in-human, first-in-class, phase I clinical trial of CNTO 888, a human monoclonal antibody to the CC-chemokine ligand 2 (CCL2) in patients (pts) with advanced solid tumors.

2548 Background: The chemokine CCL2 is highly expressed in various malignancies, and is implicated in tumor angiogenesis, proliferation, and metastasis. CCL2 orchestrates tumor-associated macrophage recruitment and osteoclastic differentiation, fostering tumorigenesis and skeletal metastases. CNTO 888 is a human IgG1κ monoclonal antibody with high CCL2 binding affinity and robust preclinical antitumor activity. Methods: CNTO 888 was administered as a 90-minute infusion on days (d) 1, 29 (for pharmacokinetic [PK] assessment) and q14d thereafter. Pre- and post-therapy pharmacodynamic [PD] evaluation included total and free CCL2 in serum, circulating tumor and endothelial cell enumeration, cytokine profiles, mandated paired tumor biopsies (n=6) for tumor CCL2, CCR2 and macrophage subtypes and exploratory diffusion contrast-enhanced computed tomography (n=6). Results: 44 pts (21M/23F) were treated with CNTO 888: 21 pts in dose-escalation cohorts (0.3, 1, 3, 10, and 15 mg/kg) and 23 pts in 2 dose-expansion cohorts (10 and 15 mg/kg). Reversible grade (G) 3 liver enzymes elevation was seen in 1 pt with progressive liver metastases. No other drug-related G3-4 adverse events (AEs) or dose-limiting toxicity (DLT) was seen. G1-2 AEs included fatigue, nausea, vomiting, pruritus, rash, and headache. PK data showed a dose-proportional increase in mean Cmax and AUC with bi- exponential decline and t1/2 of 4.4-6.9 d. Doses of 10 mg/kg q14d achieved steady-state concentrations required for antitumor activity as defined in preclinical models. Dose-dependent increases in bound CCL2 levels of >1,000-fold were demonstrated. Antitumor activity was observed in 4 pts; CA125 response and RECIST stable disease (SD) for 10 months (m) in ovarian cancer, PSA response and SD for 5m in prostate cancer, 7m SD in ocular melanoma and 15m SD in neuroendocrine tumor. Conclusions: CNTO 888 is well tolerated with no DLT. PKs are dose proportional, with evidence of PD target modulation and antitumor activity. The recommended phase II dose for single-agent CNTO 888 is 15 mg/kg q14d. Phase II studies are ongoing in prostate and planned in ovarian cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson, Ortho Biotech Johnson & Johnson Chemotherapy Foundation, Johnson & Johnson Johnson & Johnson