D J Jonker1, L S Rosen2, M B Sawyer3, F de Braud4, G Wilding5, C J Sweeney6, G C Jayson7, G A McArthur8, G Rustin9, G Goss10, J Kantor11, L Velasquez11, S Syed11, O Mokliatchouk11, D M Feltquate11, G Kollia11, D S A Nuyten11, S Galbraith11. 1. Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Canada. Electronic address: djonker@ottawahospital.on.ca. 2. Department of Oncology, Premiere Oncology, Santa Monica, USA. 3. Department of Oncology, Cross Cancer Institute, Edmonton, Canada. 4. Division of Clinical Pharmacology and New Drugs, Department of Medicine, European Institute of Oncology, Milan, Italy. 5. Department of Oncology, University of Wisconsin Carbone Cancer Center, Madison. 6. Department of Medicine, Dana-Farber Cancer Institute, Boston, USA. 7. Department of Oncology, Christie Hospital, University of Manchester, Manchester, UK. 8. Department of Medical Oncology, Peter MacCallum Cancer Center, East Melbourne, Australia. 9. Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK. 10. Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Canada. 11. Research and Development, Bristol-Myers Squibb, Princeton, USA.
Abstract
BACKGROUND: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
BACKGROUND: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
Authors: James P B O'Connor; Alan Jackson; Geoff J M Parker; Caleb Roberts; Gordon C Jayson Journal: Nat Rev Clin Oncol Date: 2012-02-14 Impact factor: 66.675
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Authors: Justine Yang Bruce; Patricia M LoRusso; Priscila H Goncalves; Elisabeth I Heath; Elizabeth Sadowski; David R Shalinsky; Yanwei Zhang; Anne M Traynor; Aurora Breazna; Alejandro D Ricart; Michael Tortorici; Glenn Liu Journal: Cancer Chemother Pharmacol Date: 2016-01-20 Impact factor: 3.333