Abstract

Abstract Background: The VEGF/VEGFR and HGF/cMet pathways are implicated in tumor survival, growth, angiogenesis, invasion and metastasis. DARPins (designed ankyrin repeat proteins) are small genetically engineered proteins that bind to specific targets with high affinity. MP0250 is a first-in-class, tri-specific DARPin with the ability to simultaneously neutralize the activities of VEGF and HGF and also to bind to human serum albumin (HSA) to give an increased plasma half-life and potentially enhanced tumor penetration. MP0250 is currently being explored in a Phase I study. Methods: A phase I, open-label, repeated-dose, dose escalation, multi-center study to assess safety, tolerability and pharmacokinetics of MP0250 is in progress in patients with advanced solid tumors who have progressed on at least one prior standard therapy. Using a 3+3 design, eligible patients are being enrolled into dose escalation cohorts receiving MP0250 by intravenous infusion every other week until disease progression or unacceptable toxicity. Results: Twelve patients have been enrolled in the first three cohorts dosed with MP0250 at 0.5 (n = 3), 1.5 (n = 3) and 4 mg/kg (n = 6). MP0250 has been well tolerated and a maximum tolerated dose has not been reached. A single dose-limiting toxicity was observed at 4mg/kg (significant reduction in cardiac ejection fraction after 1st infusion in a patient with multiple cardiac risk factors). The most frequent adverse events (AEs, CTC version 4.03) were transient hypertension (42%), diarrhea (33%), fatigue (25%) and nausea (25%). With the exception of hypertension (grade 3 in 33% of all patients), all AEs were grade 1 or 2. Interim pharmacokinetic analyses indicated linear behavior between doses 1.5 and 4 mg/kg with a mean half-life of approximately 11 days (range 9-15 days). Sustained exposure was observed for all patients throughout the treatment periods analyzed, the longest to-date being 9 months. Stable disease for 10 months (treatment ongoing) has been observed in one patient with a head and neck tumor and for 8 months in a patient with a cervical adenocarcinoma. Conclusion: Preliminary data from the Phase I study of the first-in-class, tri-specific VEGF, HGF and HSA binding DARPin MP0250 shows it to be well tolerated, to have a mean half-life around 11 days and to have sustained exposure on repeated dosing. In addition, there was disease stabilization exceeding 8 months in two patients suggestive of anti-tumor activity. Further dose escalation is ongoing. Citation Format: Jordi Rodon, Aurelius Omlin, Karin H. Herbschleb, Javier Garcia-Corbacho, Jan Steiner, Ignacio Dolado, Christof Zitt, Daniel Feurstein, Dascha Turner, Keith M. Dawson, Michael T. Stumpp, Patrick Gilboy, Andreas Harstrick, Analía Azaro, Christoph J. Ackermann, Mark R. Middleton, Richard D. Baird. First-in-human Phase I study to evaluate MP0250, a DARPin blocking HGF and VEGF, in patients with advanced solid tumors. [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 B25.

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