Work

A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours

Year: 2014

Type: article

Abstract: // David S. Hong 1 , Razelle Kurzrock 2 , Marilyn Mulay 3 , Erik Rasmussen 4 , Benjamin M. Wu 5 , Michael B. Bass 6 , Zhandong D. Zhong 7 , Greg Friberg 8 , Lee S. Rosen 9 1 Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX 77230–1402, USA 2 Center for Personalized Cancer Therapy and CTO, Division of Hematology and Oncology, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA 92093–0658, USA 3 Mulay Educational and Clinical Consulting Associates, 12412 Texas Ave., Suite 206, Los Angeles, CA 90025, USA 4 Department of Biostatistics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 5 Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 6 Department of Molecular Sciences and Computational Biology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 7 Department of Clinical Immunology and Biological Sample Management, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 8 Department of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 9 Department of Medicine, Division of Hematology and Oncology, UCLA, Santa Monica, CA 90404, USA Correspondence to: David S. Hong, e-mail: [email protected] Keywords: angiogenesis, angiopoietins, Tie2 receptor, vascular endothelial growth factor, angiogenic inhibitors Received: June 19, 2014 Accepted: October 02, 2014 Published: October 23, 2014 ABSTRACT Background: To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours. Methods: In this open-label phase 1b study, patients received IV trebananib 3 mg kg −1 QW plus bevacizumab 15 mg kg −1 Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg −1 plus bevacizumab 15 mg kg −1 (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment–related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary). Results: Thirty-six patients received ≥1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue ( n = 8), diarrhoea ( n = 4), constipation ( n = 3), nausea ( n = 3), and epistaxis ( n = 3). Three patients across those cohorts had grade ≥3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension ( n = 4), diarrhoea ( n = 4), nausea ( n = 3), fatigue ( n = 3), vomiting ( n = 2), and decreased appetite ( n = 2). Two patients had grade ≥3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months. Conclusion: Trebananib IV 3 mg kg −1 or 10 mg kg −1 plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.

Source: Oncotarget

DOI: 10.18632/oncotarget.2568