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Phase 1B Study of Motesanib, an Oral Angiogenesis Inhibitor, In Published OnlineFirst December 22, 2009; DOI: 10.1158/1078-0432.CCR-09-1675 Cancer Therapy: Clinical Clinical Cancer Research 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 George R. Blumenschein, Jr.1, Karen Reckamp2, G. Joe Stephenson3, Timothy O'Rourke4, Gregory Gladish1, Jesse McGreivy5, Yu-Nien Sun5, Yining Ye5, Mandy Parson5, and Alan Sandler6 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 car- boplatin/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 mo- tesanib [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 pulmo- nary 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 car- boplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The ob- jective 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. ©2010 AACR. In the United States, non–small cell lung cancer (NSCLC) response rates of 17% to 25%, with a median survival time accounts for nearly 85% of lung cancer cases (1), with most of ∼8 months (3, 4). Although a number of new, third- patients presenting with locally advanced (stage III) or me- generation cytotoxic therapies have become available, im- tastatic (stage IV) disease (2). Although 15% to 40% of pa- provements in outcomes for patients with advanced disease tients initially respond to cytotoxic chemotherapy, which remain modest (5), suggesting that conventional treatment remains the primary therapeutic option, long-term progno- may have reached an effectiveness plateau. sis is poor: standard-of-care treatment of advanced NSCLC Vascular endothelial growth factor (VEGF) through acti- with carboplatin in combination with paclitaxel yields vation of its receptors VEGFR1 and VEGFR2 is a potent proangiogenic factor and a key mediator of neovasculariza- tion (6) in normal and malignant tissue (7). Platelet-derived Authors' Affiliations: 1The University of Texas M.D. Anderson Cancer growth factor is thought to play a role in angiogenesis by Center, Houston, Texas; 2City of Hope Comprehensive Cancer Center, Duarte, California; 3Cancer Center of the Carolinas, Greenville, South regulating vascular survival (8) and, in NSCLC, by increas- Carolina; 4Spectrum Health, Grand Rapids, Michigan; 5Amgen Inc., ing expression of VEGF (9). Several studies have shown Thousand Oaks, California; and 6Oregon Health Sciences University, that elevated VEGF and high microvessel density are asso- Portland, Oregon ciated with poor prognosis in NSCLC (10–13) and that Corresponding Author: George R. Blumenschein, Jr., The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, VEGF may be associated with the promotion of malignant Houston, TX 77030. Phone: 713-792-6363; Fax: 713-796-8655; pleural effusion and pleural dissemination (14, 15). E-mail: [email protected]. In a separate signaling pathway, epidermal growth fac- doi: 10.1158/1078-0432.CCR-09-1675 tor receptor (EGFR) directly promotes tumor growth and ©2010 American Association for Cancer Research. survival by regulating angiogenesis and apoptosis and by www.aacrjournals.org 279 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst December 22, 2009; DOI: 10.1158/1078-0432.CCR-09-1675 Blumenschein et al. third-line metastatic colorectal cancer (28). Clinical studies Translational Relevance have suggested that combined VEGF and EGFR inhibition can improve outcomes in patients with advanced NSCLC – Non small cell lung cancer (NSCLC) remains a sig- (29, 30). The aim of the present study was to assess the nificant therapeutic challenge. Most patients present safety and pharmacokinetics and to evaluate the efficacy with advanced or metastatic disease at initial diagno- of motesanib in the treatment of NSCLC when combined sis, and traditional, chemotherapy-based treatment with cytotoxic chemotherapy and/or panitumumab. provides limited benefit. Targeted therapies blocking the pathways involved in tumor growth and survival, Materials and Methods such as the vascular endothelial growth factor and the Patients. Eligible adult (≥18 y) patients had histological- epidermal growth factor receptor pathway, have ly confirmed, unresectable stage IIIB or stage IV NSCLC emerged as important alternative treatment options. with measurable or evaluable (nonmeasurable) disease Added benefit may be achieved by combining targeted per Response Evaluation Criteria in Solid Tumors (RECIST; therapies with chemotherapy. Motesanib is a small- ref. 31). Patients either were chemotherapy-naïve (arm A molecule antagonist of the vascular endothelial growth and C) or had received no more than one prior chemo- factor receptors 1, 2, and 3, and of platelet-derived therapy regimen for NSCLC (arm B). Other key inclusion growth factor and Kit receptors. This phase 1b study criteria were Eastern Cooperative Oncology Group perfor- in patients with advanced NSCLC shows that treat- mance status of 0 or 1, life expectancy of ≥3 mo, and ad- ment with motesanib plus carboplatin/paclitaxel with equate hematologic, renal, and hepatic function. Key – or without the fully human anti epidermal growth exclusion criteria were symptomatic or untreated central factor receptor monoclonal antibody panitumumab nervous system metastases requiring concurrent treatment; was tolerable, with pharmacokinetic characteristics large (≥3 cm) central tumor lesions (located adjacent to or supporting 125-mg once-daily dosing of motesanib within the hilum or mediastinum) of squamous cell his- as combination therapy. By blocking multiple signal- tology unless treated by central irradiation; uncontrolled ing pathways, motesanib may represent a novel tar- hypertension; history of arterial or venous thrombosis, geted treatment approach for advanced NSCLC. bleeding diathesis, pulmonary hemorrhage, gross hemop- tysis, or ischemic heart disease; systemic chemotherapy, ra- diation therapy, or antibody therapy within 14, 21 d, or 6 wk of study enrollment, respectively; or treatment with increasing expression of VEGF (16, 17). Expression of any anti-VEGF or anti-EGFR therapy. All patients provided EGFR mRNA in tumor tissue from patients with NSCLC written informed consent before any study-related proce- has been correlated with survival (18). dures were done. VEGFanditsreceptorsaswellastheEGFRsignaling Study design. This was a multicenter (conducted in six cascade are now two validated molecular targets for the centers in the United States), open-label, dose-finding, development of novel treatment options for patients with phase 1b study of motesanib (Amgen Inc.) administered advanced NSCLC, as shown in the Eastern Cooperative in combination with carboplatin/paclitaxel as first-line Oncology Group study E4599 (19), the Avastin in Lung treatment (arm A), with panitumumab as second-line treat- (AVAIL) study (20), and the First-Line Treatment for Pa- ment (arm B), or with carboplatin/paclitaxel and panitu- tients with EGFR-expressing Advanced NSCLC (FLEX) mumab as first-line treatment (arm C) in patients with study (21). Currently, the anti-VEGF monoclonal anti- advanced NSCLC. Primary end points were the incidence body bevacizumab in combination with carboplatin and of treatment-related adverse events and dose-limiting toxi- paclitaxel is approved for the first-line treatment of ad- cities (DLT) and determination of the motesanib pharma- vanced or metastatic nonsquamous NSCLC (19); the cokinetic profile in the three treatment arms. Secondary end EGFR inhibitor erlotinib is approved for second- or points included paclitaxel and motesanib exposure [maxi- third-line treatment of NSCLC (22). Other antiangiogenic mum observed plasma concentration (Cmax) and area un- agents have been evaluated as first-line treatment in the der the concentration-time curve (AUC)] when motesanib setting of advanced NSCLC but thus far have failed to and carboplatin/paclitaxel were administered
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