Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib

BMC Cancer

Noriyuki Koyama¹  Kenichi Saito⁶  Yuki Nishioka⁴  Wataru Yusa⁵  Noboru Yamamoto²  Yasuhide Yamada⁷  Hiroshi Nokihara²  Fumiaki Koizumi⁸  Kazuto Nishio³  Tomohide Tamura² 

[1] Oncology Medical Department, Eisai Co, Ltd, Tokyo, Japan

[2] Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

[3] Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan

[4] Japan Clinical Pharmacology/Clinical Pharmacology/Clinical Science, Scientific and Operation Clinical Support Core Function Unit, Eisai Co, Ltd, Tokyo, Japan

[5] Oncology Clinical Development Section, Japan/Asia Clinical Research Production Creation Unit, Eisai Co, Ltd, Tokyo, Japan

[6] Japan Biostatistics/Biostatistics/Clinical Science, Scientific and Operational Clinical Support Core Function Unit, Eisai Co, Ltd, Tokyo, Japan

[7] Department of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan

[8] Shien-Lab and Support Facility of Project Ward, National Cancer Center Hospital, Tokyo, Japan

关键词: Maximum tumor shrinkage;    sVEGFR2;    SDF1α;    VEGF;    Pharmacodynamic biomarkers;    Angiogenesis;    Lenvatinib;   

Others  :  1125311
DOI  :  10.1186/1471-2407-14-530

 received in 2013-11-19, accepted in 2014-07-03,  发布年份 2014

【 摘 要 】

Background

Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.

Methods

Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.

Results

Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1α] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1α, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1α levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.

Conclusion

PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.

Trial registration

ClinicalTrial.gov: NCT00280397 (January 20, 2006).

【 授权许可】

   
2014 Koyama et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Rapisarda A, Melillo G: Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 2012, 9:378-390.
• [2]Yamamoto N, Tamura T, Yamamoto N, Yamada K, Yamada Y, Nokihara H, Fujiwara Y, Takahashi T, Murakami H, Boku N, Yamazaki K, Puchalski TA, Shin E: Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2009, 64:1165-1172.
• [3]Fujisaka Y, Yamada Y, Yamamoto N, Shimizu T, Fujiwara Y, Yamada K, Tamura T, Watanabe H, Sun YN, Bass MB, Seki M: Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2010, 66:935-943.
• [4]Asahina H, Tamura Y, Nokihara H, Yamamoto N, Seki Y, Shibata T, Goto Y, Tanioka M, Yamada Y, Coates A, Chiu YL, Li X, Pradhan R, Ansell PJ, McKeegan EM, McKee MD, Carlson DM, Tamura T: An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 2012, 69:1477-1486.
• [5]Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ: The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 2013, 15:807-817.
• [6]Loges S, Schmidt T, Carmeliet P: Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer 2010, 1:12-25.
• [7]Ebos JM, Lee CR, Kerbel RS: Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 2009, 15:5020-5025.
• [8]Sennino B, McDonald DM: Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 2012, 12:699-709.
• [9]Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N: Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1+ myeloid cells. Nat Biotechnol 2007, 25:911-920.
• [10]Yao JC, Phan A: Overcoming antiangiogenic resistance. Clin Cancer Res 2011, 17:5217-5219.
• [11]Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS: Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 2007, 104:17069-17074.
• [12]Mutsaers AJ, Francia G, Man S, Lee CR, Ebos JM, Wu Y, Witte L, Berry S, Moore M, Kerbel RS: Dose-dependent increases in circulating TGF-alpha and other EGFR ligands act as pharmacodynamic markers for optimal biological dosing of cetuximab and are tumor independent. Clin Cancer Res 2009, 15:2397-2405.
• [13]Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M: Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008, 14:5459-5465.
• [14]Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, Uenaka T, Asada M: E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008, 122:664-671.
• [15]Ikuta K, Yano S, Trung VT, Hanibuchi M, Goto H, Li Q, Wang W, Yamada T, Ogino H, Kakiuchi S, Uehara H, Sekido Y, Uenaka T, Nishoka Y, Sone S: E7080, a multi–tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles. Clin Cancer Res 2009, 15:7229-7239.
• [16]Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, Copalu W, Mazur A, Wanders J, O’Brien JP, Schellens JH, Evans TR: A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer 2012, 106:1598-1604.
• [17]Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, Hirata T, Koizumi F, Nishio K, Koyama N, Tamura T: Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res 2011, 17:2528-2537.
• [18]Sherman SI, Jarzab B, Cabanillas ME, Licitra LF, Pacini F, Martins R, Robinson B, Ball D, McCaffrey J, Shah MH, Bodenner D, Allison R, Newbold K, Elisei R, O’Brien JP, Schlumberger M: A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) [abstract]. J Clin Oncol 2011, 29(suppl):5503.
• [19]Keizer RJ, Gupta A, Shumaker R, Beijnen JH, Schellens JH, Huitema AD: Model-based treatment optimization of a novel VEGFR inhibitor. Br J Clin Pharmacol 2012, 74:315-326.
• [20]Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MD, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000, 92:205-216.
• [21]Zhu X, Wu S, Dahut WL, Parikh CR: Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 2007, 49:186-193.
• [22]Robinson ES, Matulonis UA, Ivy P, Berlin ST, Tyburski K, Penson RT, Humphreys BD: Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor. Clin J Am Soc Nephrol 2010, 5:477-483.
• [23]Ferrara N: Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000, 55:15-35.
• [24]Makino H, Aoki M, Hashiya N, Yamasaki K, Azuma J, Sawa Y, Kaneda Y, Ogihara T, Morishita R: Long-term follow-up evaluation of results from clinical trial using hepatocyte growth factor gene to treat severe peripheral arterial disease. Arterioscler Thromb Vasc Biol 2012, 32:2503-2509.
• [25]Guo Y, Su L, Li Y, Guo N, Xie L, Zhang D, Zhang X, Li H, Zhang G, Wang Y, Liu C: The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats. Heart Vessels 2013. Aug 10: Epub ahead of print
• [26]Mills PJ, Parker B, Dimsdale JE, Sadler GR, Ancoli-Israel S: The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer. Biol Psychol 2005, 69:85-96.
• [27]Kanehisa M, Ishitobi Y, Ando T, Okamoto S, Maruyama Y, Kohno K, Ninomiya T, Higuma H, Tanaka Y, Tsuru J, Hanada H, Kodama K, Akiyoshi J: Serum hepatocyte growth factor levels and the effects of antidepressants in panic disorder. Neuropeptides 2010, 44:431-435.
• [28]Ravaud A, Schmidinger M: Clinical biomarkers of response in advanced renal cell carcinoma. Ann Oncol 2013, 24:2935-2942.
• [29]Rutkowski P, Bylina E, Klimczak A, Switaj T, Falkowski S, Kroc J, Lugowska I, Brzeskwiniewicz M, Melerowicz W, Osuch C, Mierzejewska E, Wasielewski K, Woźniak A, Grzesiakowska U, Nowecki ZI, Siedlecki JA, Limon J: The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. BMC Cancer 2012, 12:107.
• [30]Yang Y, Zhang Y, Cao Z, Ji H, Yang X, Iwamoto H, Wahlberg E, Länne T, Sun B, Cao Y: Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc Natl Acad Sci U S A 2013, 110:12018-12023.
• [31]Fujiwara Y, Kiyota N, Chayahara N, Suzuki A, Umeyama Y, Mukohara T, Minami H: Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients. Invest New Drugs 2012, 30:1055-1064.
• [32]Noda M, Omatsu Y, Sugiyama T, Oishi S, Fujii N, Nagasawa T: CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice. Blood 2011, 117:451-458.
• [33]Williams SA, Harata-Lee Y, Comerford I, Anderson RL, Smyth MJ, McColl SR: Multiple functions of CXCL12 in a syngeneic model of breast cancer. Mol Cancer 2010, 9:250.
• [34]Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, Batchelor TT, Sorensen AG: Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 2009, 6:327-338.
• [35]Ferrara N: Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004, 9(Suppl 1):2-10.
• [36]Thomas CP, Andrews JI, Liu KZ: Intronic polyadenylation signal sequences and alternate splicing generate human soluble Flt1 variants and regulate the abundance of soluble Flt1 in the placenta. FASEB J 2007, 21:3885-3895.
• [37]Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J: Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 2009, 15:1023-1030.
• [38]Zhu AX, Ancukiewicz M, Supko JG, Sahani DV, Blaszkowsky LS, Meyerhardt JA, Abrams TA, McCleary NJ, Bhargava P, Muzikansky A, Sheehan S, Regan E, Vasudev E, Knowles M, Fuchs CS, Ryan DP, Jain RK, Duda DG: Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. Clin Cancer Res 2013, 19:1557-1566.
• [39]Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007, 11:83-95.
• [40]Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006, 24:16-24.
• [41]Tomita Y, Uemura H, Fujimoto H, Kanayama HO, Shinohara N, Nakazawa H, Imai K, Umeyama Y, Ozono S, Naito S, Akaza H: Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: a phase II study in Japanese patients with cytokine-refractory metastatic renal cell carcinoma. Eur J Cancer 2011, 47:2592-2602.
• [42]Jesmin S, Wada T, Gando S, Sultana SS, Zaedi S: The dynamics of angiogenic factors and their soluble receptors in relation to organ dysfunction in disseminated intravascular coagulation associated with sepsis. Inflammation 2013, 36:186-196.
• [43]Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM: Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009, 27:3312-3318.
• [44]Llovet JM, Peña CE, Lathia CD, Shan M, Meinhardt G, Bruix J: Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2012, 18:2290-2300.
• [45]Harmon CS, DePrimo SE, Figlin RA, Hudes GR, Hutson TE, Michaelson MD, Négrier S, Kim ST, Huang X, Williams JA, Eisen T, Motzer RJ: Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma. Cancer Chemother Pharmacol 2014, 73:151-161.
• [46]Horsley L, Marti K, Jayson GC: Is the toxicity of anti-angiogenic drugs predictive of outcome? A review of hypertension and proteinuria as biomarkers of response to anti-angiogenic therapy. Expert Opin Drug Metab Toxicol 2012, 8:283-293.
• [47]Nishio M, Horai T, Horiike A, Nokihara H, Yamamoto N, Takahashi T, Murakami H, Yamamoto N, Koizumi F, Nishio K, Yusa W, Koyama N, Tamura T: Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. Br J Cancer 2013, 109:538-544.