Phase 1b Study of Motesanib, an Oral Angiogenesis Inhibitor, in Combination with Carboplatin/Paclitaxel and/or Panitumumab for the Treatment of Advanced Non–Small Cell Lung Cancer

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Abstract
Purpose: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti–epidermal growth factor receptor monoclonal antibody panitumumab in advanced non–small cell lung cancer (NSCLC). Experimental Design: Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). Results: Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively. Conclusions: Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC. Clin Cancer Res; 16(1); 279–90

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