The VEGF/VEGFR and HGF/cMet pathways are implicated in tumor survival, growth, angiogenesis, invasion and metastasis. DARPins® (designed ankyrin repeat proteins) are small proteins that can be engineered to bind to specific targets with high specificity and affinity. MP0250 is a first-in-class, tri-specific multi-DARPin® neutralizing VEGF and HGF as well as binding to human serum albumin to increase plasma half-life and potentially enhance tumor penetration.
A phase I, open-label, multi-center study with completed dose escalation. Eligibility: patients with advanced solid tumors. Design: 3 + 3 dose escalation cohorts receiving intravenous MP0250 every 2 weeks.
A total of 24 patients have been enrolled in 5 cohorts: 0.5 (n = 3), 1.5 (n = 3), 4 (n = 6), 8 (n = 7), or 12 mg/kg (n = 5) MP0250. The maximum tolerated dose was determined as 8 mg/kg. At 12mg/kg, 2 DLTs were observed in line with expected anti-VEGF activity: a grade 3 (CTC v4.03) GI hemorrhage and a grade 3 nephrotic syndrome plus grade 3 hypertension. Other AEs of special interest were: grade 3 pulmonary embolism (2pts), grade 3 left ventricular failure, grade 4 thrombotic microangiopathy (1pt each). The only grade 3 AE occurring in >10% of pts was hypertension (33%). The most frequent AEs, irrespective of relation to study drug, were hypertension (63% of pts), diarrhea (46%), fatigue (46%), cough (33%), nausea (29%), proteinuria, anorexia, and vomiting (25% each). Pharmacokinetic analyses show dose-dependent AUC and Cmax increases and sustained exposure over multiple cycles with a mean half-life of 12 days. Signs of clinical activity were observed. Two patients showed significant reductions in tumor volume (1 confirmed as partial response). In addition, prolonged stable disease was seen in 4 patients (between 22 and 60 weeks).
MP0250 showed a favorable PK profile and is well tolerated with most AEs being consistent with profound inhibition of the VEGF pathway. Signs of clinical activity were seen. Expansion cohorts are planned and ongoing. Phase 2 studies in selected oncology indications including multiple myeloma are planned.
Clinical trial identification
Legal entity responsible for the study
M.R. Middleton: Consultant and/or Research support: Abbvie, Amgen, AZ, BMS, Clovis, Eisai, GSK, Immucore, Lilly, Merck, Millenium, Novartis, Physiomics, Rigontec, Roche, Molecular Partners, Pfizer, Vertex (all to institution). J. Rodón: Novartis; Eli Lilly; Servier; Leti Pharma. C. Zitt, D. Feurstein, S. Schreiner, D. Turner, K. Dawson, K. Tadjalli-Mehr, E. vom Baur, M. Stumpp, A. Harstrick: Molecular Partners stock. A. Omlin: Travel support; Bayer; Travel support; Sanofi; Janssen; Travel support; Astellas; Pfizer; AstraZeneca; Teva. Research support: Janssen, Teva. All other authors have declared no conflicts of interest.
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