Abstract C119: Investigation of the anti-angiogenic effects of abituzumab in patients with colorectal or ovarian cancer and liver metastases using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)

Abstract

Abstract Background: Integrins promote cell survival, metastasis, and angiogenesis, with integrins ανβ3 and ανβ5 promoting neovascularization. Abituzumab (EMD 525797) is a humanized monoclonal IgG2 antibody that specifically binds to the αν integrin subunit to inhibit αν integrin-mediated functions. It has shown antitumor activity in preclinical models and clinical trials. We investigated the tolerability and potential anti-angiogenic activity of abituzumab using DCE-MRI. Methods: This phase I study recruited patients (pts) ≥18 years with liver metastases (3-10 cm in diameter) of either colorectal (CRC) or ovarian cancer (OC) who had failed standard therapy. Pts received abituzumab 250, 500, 1,000, or 1,500 mg IV q2w, with ≥6 pts per dose. The decision to escalate the dose was based on the occurrence of dose-limiting toxicity (DLT). DCE-MRI scans were performed 24 and 96 hours after the first abituzumab dose, 1 week after first dose, and immediately prior to the second dose to identify changes in parameters including Ktrans, extracellular/extravascular volume, and blood plasma volume during one cycle of therapy. DCE-MRI scan data were analyzed centrally. Tumor response was evaluated every 6 weeks. Primary objectives were to assess the tolerability of abituzumab and to investigate vascular and volumetric responses to abituzumab using DCE-MRI. Secondary objectives included characterization of the pharmacokinetics of abituzumab and its effect on exploratory pharmacodynamic markers, including tumor markers. Results: 41 pts were enrolled (CRC, n = 30; OC, n = 11). All pts had received ≥1 prior anticancer treatment. Four of 31 pts included in the dose-escalation analysis set had DLTs: myocardial ischemia (250 mg, n = 1/6), intracranial hemorrhage (500 mg, n = 1/12), and drug hypersensitivity (1,500 mg, n = 2/7). With the exception of drug hypersensitivity, the nature and incidence of adverse events (AEs) were similar between the dose levels. The most frequently reported treatment-related AEs were fatigue (12.2%) and headache (12.2%). Of 32 patients with available response information, 3 with OC had a best overall response of stable disease (SD) lasting ≥6 weeks (2 treated with abituzumab 500 mg, 1 with abituzumab 1,000 mg); one 73-year-old pt with high-grade serous OC who received abituzumab as 5th-line therapy had SD for 33 weeks and a CA-125 response. No complete or partial responses were observed. No trends in differences in mean DCE-MRI parameters between abituzumab doses and no vascular or volumetric responses to abituzumab were observed, although alterations in DCE-MRI parameters were noted in individual patients. Small changes in IAUC60, Ktrans, and blood plasma volume were observed between Week 1 Day 5 and Week 2 Day 1 that may have been due to abituzumab-induced effects, but did not correlate with clinical activity (SD). Conclusions: This phase I trial has confirmed the tolerability of abituzumab, although hypersensitivity reactions represent a new event that warrants further investigation. The occurrence of SD in pts with OC with large liver metastases suggests that abituzumab has activity. However, there was little evidence of a clear effect of abituzumab on tumor vasculature, suggesting limited dependence on neovascularization in advanced tumors. Citation Format: Josep Tabernero, Geoffrey Parker, Andrew Clamp, Elena Elez, Nerissa Mescallado, Rodrigo Dienstmann, Tamara Sauri, Jurjees Hasan, Jose J. Mateos, Rolf Bruns, Claude Gimmi, Gordon C. Jayson. Investigation of the anti-angiogenic effects of abituzumab in patients with colorectal or ovarian cancer and liver metastases using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C119.