Clinical Research Papers:
A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours
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David S. Hong1, Razelle Kurzrock2, Marilyn Mulay3, Erik Rasmussen4, Benjamin M. Wu5, Michael B. Bass6, Zhandong D. Zhong7, Greg Friberg8, Lee S. Rosen9
1Department 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
2Center 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
3Mulay Educational and Clinical Consulting Associates, 12412 Texas Ave., Suite 206, Los Angeles, CA 90025, USA
4Department of Biostatistics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
5Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
6Department of Molecular Sciences and Computational Biology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
7Department of Clinical Immunology and Biological Sample Management, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
8Department of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
9Department of Medicine, Division of Hematology and Oncology, UCLA, Santa Monica, CA 90404, USA
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
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.
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