Motesanib

1 . De Boer RH, Kotasek D, White S, Koczwara B, Mainwaring P, Chan A, Melara R, Ye Y, Adewoye AH, Sikorski R, Kaufman PA.Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.Breast Cancer Res Treat. 2012 Aug;135(1):241-52. Epub 2012 Jul 29.
Abstract
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.

2 . Coxon A, Bready J, Kaufman S, Estrada J, Osgood T, Canon J, Wang L, Radinsky R, Kendall R, Hughes P, Polverino A.Anti-tumor activity of motesanib in a medullary thyroid cancer model.J Endocrinol Invest. 2012 Feb;35(2):181-90. Epub 2011 Mar 21.
Abstract
BACKGROUND: Medullary thyroid cancer (MTC) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Motesanib is an investigational, orally administered small molecule antagonist of VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR); Kit; and possibly Ret. AIM: The aim of this study was to investigate the effects of motesanib on wildtype and mutant Ret activity in vitro and on tumor xenograft growth in a mouse model of MTC...

3 . Martin M, Roche H, Pinter T, Crown J, Kennedy MJ, Provencher L, Priou F, Eiermann W, Adrover E, Lang I, Ramos M, Latreille J, Jagie??o-Gruszfeld A, Pienkowski T, Alba E, Snyder R, Almel S, Rolski J, Munoz M, Moroose R, Hurvitz S, Ba?os A, Adewoye H, Hei YJ, Lindsay MA, Rupin M, Cabaribere D, Lemmerick Y, Mackey JR; TRIO 010 investigators.Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.Lancet Oncol. 2011 Apr;12(4):369-76. Epub 2011 Mar 21.
Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681...

4 . Polverino, Anthony et al AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Research (2006), 66(17), 8715-8721.
Abstract
The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical model...

5 . Rosen, Lee S. et al Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. Journal of Clinical Oncology (2007), 25(17), 2369-2376.
Abstract
Purpose AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors. Patients and Methods AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determine...