Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-Cisplatin in patients with advanced cancer

Howard Burris, Joe Stephenson, Gregory A Otterson, Mark Stein, Jesse McGreivy, Yu-Nien Sun, Megan Ingram, Yining Ye, Lee S Schwartzberg, Howard Burris, Joe Stephenson, Gregory A Otterson, Mark Stein, Jesse McGreivy, Yu-Nien Sun, Megan Ingram, Yining Ye, Lee S Schwartzberg

Abstract

Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m(2)) and cisplatin (75 mg/m(2)) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.

Figures

Figure 1
Figure 1
Study schema.
Figure 2
Figure 2
Mean plasma concentration-versus-time profiles of motesanib following once- or twice-daily oral administration in combination with panitumumab and gemcitabine/cisplatin chemotherapy. Data are mean (±SD). aDifferent n due to missing or excluded values. BID: twice daily; QD: once daily.

References

    1. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438(7070):932–936.
    1. Folkman J. Role of angiogenesis in tumor growth and metastasis. Seminars in oncology. 2002;29(6):15–18.
    1. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature Medicine. 2003;9(6):669–676.
    1. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. Journal of Clinical Oncology. 2006;24(26):4293–4300.
    1. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. Journal of the American Medical Association. 2006;295(21):2516–2524.
    1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New England Journal of Medicine. 2006;355(24):2542–2550.
    1. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. Journal of Clinical Oncology. 2002;20(6):1692–1703.
    1. Yu J, Ustach C, Kim HRC. Platelet-derived growth factor signaling and human cancer. Journal of Biochemistry and Molecular Biology. 2003;36(1):49–59.
    1. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. The Lancet. 2006;368(9544):1329–1338.
    1. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. The Lancet. 2004;364(9440):1127–1134.
    1. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. The Lancet. 2009;373(9674):1525–1531.
    1. Herbst RS, O’Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer. Journal of Clinical Oncology. 2007;25(30):4743–4750.
    1. Polverino A, Coxon A, Starnes C, 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.
    1. Rosen LS, Kurzrock R, Mulay M, 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.
    1. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. Journal of Clinical Oncology. 2009;27(23):3794–3801.
    1. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. New England Journal of Medicine. 2008;359(1):31–42.
    1. Blumenschein GR, Jr., Reckamp K, Stephenson GJ, et al. 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. Clinical Cancer Research. 2010;16(1):279–290.
    1. Kaufman PA, de Boer R, White S, et al. Phase 1b study of motesanib diphosphate (AMG 706) in combination with paclitaxel or docetaxel for the treatment of locally recurrent, unresectable or metastatic breast cancer. In: Proceedings of the San Antonio Breast Cancer Symposium; December 2008; San Antonio, Tex, USA. asbtract 4117.
    1. Price TJ, Lipton L, McGreivy J, McCoy S, Sun YN, Rosenthal MA. Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours. British Journal of Cancer. 2008;99(9):1387–1394.
    1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. Journal of the National Cancer Institute. 2000;92(3):205–216.
    1. Eskens FALM, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. European Journal of Cancer. 2006;42(18):3127–3139.
    1. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine. 2004;350(23):2335–2342.
    1. Hainsworth J, Herbst R. A phase III, multicenter, placebo-controlled, double-blind, randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin) in combination with erlotinib (Tarceva) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA) Journal of Thoracic Oncology. 2008;3:p. S302.
    1. Miller VA, O’Connor P, Soh C, Kabbinavar F, Investigators A. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) Journal of Clinical Oncology. 2009;27, article LBA8002
    1. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. Journal of Clinical Oncology. 2005;23(24):5474–5483.
    1. Thomas AL, Morgan B, Horsfield MA, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. Journal of Clinical Oncology. 2005;23(18):4162–4171.
    1. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. Journal of Clinical Oncology. 2004;22(11):2184–2191.
    1. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. Journal of Clinical Oncology. 2009;27(5):672–680.
    1. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. New England Journal of Medicine. 2009;360(6):563–572.
    1. Tol J, Koopman M, Rodenburg CJ, et al. A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Annals of Oncology. 2008;19(4):734–738.
    1. Meyerhardt JA, Stuart K, Fuchs CS, et al. Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastastic colorectal cancer. Annals of Oncology. 2007;18(7):1185–1189.
    1. Berlin J, Posey J, Tchekmedyian S, et al. Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clinical Colorectal Cancer. 2007;6(6):427–432.
    1. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology. 2007;25(15):1960–1966.
    1. Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: southwest oncology group-directed intergroup trial S0205. Journal of Clinical Oncology. 2010;28(22):3605–3610.
    1. Marshall JL. Vascular endothelial growth factor plus epidermal growth factor receptor dual targeted therapy in metastatic colorectal cancer: Synergy or antagonism? Journal of Oncology. 2009;2009:9 pages. Article ID 937305.
    1. Van Cutsem E, Siena S, Humblet Y, et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Annals of Oncology. 2008;19(1):92–98.
    1. Peeters M, Price TJ, Hotko YS, et al. Randomized phase III study of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC): patient-reported outcomes (PRO). In: Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 2010; Orlando, Fla, USA.
    1. Siena S, Cassidy J, Tabernero J, et al. Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): PRIME trial. In: Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 2010; Orlando, Fla, USA.
    1. Barceló R, Munoz A, López-Vivanco G, Numico G, Merlano M, Silvestris N. Prospective evaluation of major vascular events in patients with nonsmall cell lung carcinoma treated with cisplatin and gemcitabine. Cancer. 2005;104(5):1110–1111.
    1. Kuenen BC, Rosen L, Smit EF, et al. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. Journal of Clinical Oncology. 2002;20(6):1657–1667.
    1. Li C, Kuchimanchi M, Hickman D, et al. In vitro metabolism of the novel, highly selective oral angiogenesis inhibitor motesanib diphosphate in preclinical species and in humans. Drug Metabolism and Disposition. 2009;37(7):1378–1394.
    1. Andersson A, Fagerberg J, Lewensohn R, Ehrsson H. Pharmacokinetics of cisplatin and its monohydrated complex in humans. Journal of Pharmaceutical Sciences. 1996;85(8):824–827.
    1. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Annals of Oncology. 2006;17(5):v7–v12.
    1. Tabrizi MA, Tseng CML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discovery Today. 2006;11(1-2):81–88.

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