TY - JOUR
T1 - First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors
AU - Moore, Kathleen N.
AU - Bendell, Johanna C.
AU - LoRusso, Patricia M.
AU - Olszanski, Anthony J.
AU - Zwick-Wallasch, Esther
AU - Jansen, Mendel
AU - Vandell, Alexander G.
AU - Senaldi, Giorgio
N1 - Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/2/15
Y1 - 2019/2/15
N2 - U3–1565 is a monoclonal antibody directed against heparin-binding epidermal growth factor-like growth factor (HB-EGF), which mediates angiogenesis via induction of vascular endothelial growth factor (VEGF-A). This first-in-human study characterized the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of U3–1565 in subjects with advanced solid tumors. In Part 1 (dose escalation following a modified 3 + 3 design), Cohorts 1–4, U3–1565 was administered at 2, 8, 16, and 24 mg/kg every 3 weeks for Cycle 1 and every 2 weeks thereafter. In Part 1, Cohort 5, and in Part 2 (dose expansion), U3–1565 was administered at 24 mg/kg every week. Thirty-six subjects were enrolled and treated (15 in Part 1; 21 in Part 2). No subject experienced dose limiting toxicity and maximum tolerated dose was not reached. All drug-related events were Grade 1 or 2 in severity, with fatigue and rash predominating. Following treatment with U3–1565, 1 subject with metastatic colorectal cancer experienced partial response and 6 subjects achieved stable disease. Four subjects completed the study main phase (first 12 cycles) and entered the extension phase. Of the 6/36 subjects with high (> 1500 pg/ml) baseline VEGF-A levels, all showed a decrease in VEGF-A (median − 60% [−22% to −97%]). Of the remaining subjects, only 19/30 showed a decrease (median − 18% [−2% to −82%]). Subjects with high VEGF-A baseline levels remained on treatment longer (3/6 entered study extension phase versus 1/30), and were more likely to show disease control (3/6 versus 4/30). In conclusion, U3–1565 demonstrates both proof of mechanism and clinical activity across different tumor types.
AB - U3–1565 is a monoclonal antibody directed against heparin-binding epidermal growth factor-like growth factor (HB-EGF), which mediates angiogenesis via induction of vascular endothelial growth factor (VEGF-A). This first-in-human study characterized the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of U3–1565 in subjects with advanced solid tumors. In Part 1 (dose escalation following a modified 3 + 3 design), Cohorts 1–4, U3–1565 was administered at 2, 8, 16, and 24 mg/kg every 3 weeks for Cycle 1 and every 2 weeks thereafter. In Part 1, Cohort 5, and in Part 2 (dose expansion), U3–1565 was administered at 24 mg/kg every week. Thirty-six subjects were enrolled and treated (15 in Part 1; 21 in Part 2). No subject experienced dose limiting toxicity and maximum tolerated dose was not reached. All drug-related events were Grade 1 or 2 in severity, with fatigue and rash predominating. Following treatment with U3–1565, 1 subject with metastatic colorectal cancer experienced partial response and 6 subjects achieved stable disease. Four subjects completed the study main phase (first 12 cycles) and entered the extension phase. Of the 6/36 subjects with high (> 1500 pg/ml) baseline VEGF-A levels, all showed a decrease in VEGF-A (median − 60% [−22% to −97%]). Of the remaining subjects, only 19/30 showed a decrease (median − 18% [−2% to −82%]). Subjects with high VEGF-A baseline levels remained on treatment longer (3/6 entered study extension phase versus 1/30), and were more likely to show disease control (3/6 versus 4/30). In conclusion, U3–1565 demonstrates both proof of mechanism and clinical activity across different tumor types.
KW - HB-EGF
KW - Pharmacokinetics
KW - Phase 1
KW - U3–1565
KW - VEGF-A
UR - http://www.scopus.com/inward/record.url?scp=85050737522&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000460846400016&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1007/s10637-018-0646-1
DO - 10.1007/s10637-018-0646-1
M3 - Article
C2 - 30056611
SN - 0167-6997
VL - 37
SP - 147
EP - 158
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -