Phase I and pharmacokinetic study of etaracizumab (Abegrin™), a humanized monoclonal antibody against αvβ3 integrin receptor, in patients with advanced solid tumors

Abstract

This study assessed the safety, immunogenicity, and pharmacokinetics of etaracizumab, a monoclonal antibody directed against the alphavbeta3 integrin, in patients with advanced malignancies. Four cohorts of four patients received escalating dose of etaracizumab as a 30-min intravenous infusion, first as a single test dose, followed-up 2-5 weeks later by weekly doses. Sixteen patients with advanced solid tumors received a total of 309 cycles of etaracizumab at doses ranging 1-6 mg/kg. The mean number of weekly infusions was 19 (ranging 5-53). Frequently reported adverse events were grades 1-2 asthenia (15 patients) and infusion reactions (9 patients). At 1 mg/kg, one patient experienced grade 3 chills with the first infusion. Other grade 3 toxicities included reversible hyponatremia, hypophosphatemia and hyponatremia in one patient each at 1, 4 and 6 mg/kg, respectively. No patient experienced treatment delay/discontinuation due to an adverse event. The half-life of etaracizumab ranged 49-180 h with a nonlinear increase in terminal half-life with increasing doses. There was no objective response but five patients experienced a stable disease of >6-month duration. Etaracizumab was well-tolerated at doses up to 6 mg/kg with no evidence of immunogenicity. The safety profile of etaracizumab warrants further exploration in ongoing phase I/II trials.

Integrin αvβ3‐targeted cancer therapy

“…[Jain, 2005]. [Color figure can be viewed in the online version] [Delbaldo et al, 2008;Patel et al, 2001;Posey et al, 2001] Phase II [Beekman et al, 2006;Colevas et al, 2004;Hariharan et al, 2007;MacDonald et al, 2008;Nabors et al, 2007;Raguse et al, 2004] ATN-161 Ac-PHSCN-NH 2 α 5 β 1 , α v β 3 Phase II [Cianfrocca et al, 2006;Donate et al, 2008] …”

β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication (Review)

“…In clinical trials, etaracizumab also demonstrated antiangiogenic activity, low toxicity and disease stabilization in patients with certain types of cancer (48,49). In addition, in preclinical and clinical trials, volociximab, a function-blocking monoclonal antibody against integrin α5β1, has exhibited efficacy in inhibiting angiogenesis and tumor growth (42,50).…”

Integrins as therapeutic targets: lessons and opportunities

“…It also plays a key role in metastasis where its expression in melanoma is associated with highly metastatic disease 58 . Etaracizumab is a monoclonal antibody to α V β 3 that is undergoing early clinical development for treatment of melanoma [59][60] and solid tumours 61 . The cyclic-RGD peptide cilengitide is a specific α V β 3 antagonist and is currently under going clinical trials for use in glioblastoma [62][63] and in other brain cancers 64 and has recently become the first anti-integrin to enter Phase III trials for cancer 65 .…”