First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody-Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer

Sung-Bae Kim, Funda Meric-Bernstam, Aparna Kalyan, Aleksei Babich, Rong Liu, Takahiko Tanigawa, Anette Sommer, Motonobu Osada, Frank Reetz, Dirk Laurent, Sabine Wittemer-Rump, Jordan Berlin, Sung-Bae Kim, Funda Meric-Bernstam, Aparna Kalyan, Aleksei Babich, Rong Liu, Takahiko Tanigawa, Anette Sommer, Motonobu Osada, Frank Reetz, Dirk Laurent, Sabine Wittemer-Rump, Jordan Berlin

Abstract

Background: Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody-drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload.

Objective: This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive.

Patients and methods: In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin.

Results: Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1-1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported.

Conclusions: Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. CLINICALTRIALS.

Gov identifier: NCT02368951.

Conflict of interest statement

A. Sommer, F. Reetz, A. Babich, S. Wittemer-Rump, and R. Liu are shareholders and employees of Bayer AG. T. Tanigawa is an employee of Bayer Yakuhin. M. Osada and D. Laurent were employees of Bayer AG, Berlin, Germany, during the conduct of the study. M. Osada now works at Merck Serono, Tokyo, Japan. D. Laurent now works at Berlin-Chemie, Berlin, Germany. S.-B. Kim reports receiving institutional research funding from Novartis, Sanofi-Genzyme, Kyowa Kirin Inc., and Dongkook Pharma Co Ltd. F. Meric-Bernstam reports receiving commercial research grants from Novartis, AstraZeneca, Taiho, Genentech, Calithera, Debio International Group, Bayer, PUMA, Aileron, Jounce, CytoMx, Effector, Zymeworks, Curis, and Pfizer, and is a consultant/advisory board member for Dialecta, Sumitomo Dainippon, Pieris Pharmaceuticals, Darwin Health, Samsung Bioepis, Aduro, Spectrum, OrigiMed, Debiopharm International, Inflection Biosciences, Xencor, and Genentech. J. Berlin reports consultancy fees and institutional research funding from Genentech, EMD Serono, 5Prime, BeiGene, Karyopharm, and Symphogen, honoraria from Nestlé Health Science, consultancy fees from Celgene, Cornerstone, Exelis, Gritstone Oncology, ERYTECH Pharma, AstraZeneca, Arno Therapeutics, Symphogen, Abbvie, and Eisai, and institutional research funding from Immunomedics, Gilead, Taiho, Loxo, Bayer, Incyte, and Pharmacyclics. A. Kalyan reports advisory boards for BMS, Exelis, Ipsen, and Eisai.

Figures

Fig. 1
Fig. 1
Patient disposition and analysis population
Fig. 2
Fig. 2
Geometric mean plasma concentrations of a aprutumab ixadotin, b total antibody, and c toxophore metabolite (BAY 1159184) during cycle 1 for the 0.1 (n = 4), 0.2, 0.4 (n = 3), 0.8 (n = 4), and 1.3 (n = 5) mg/kg dose cohorts. Data for the toxophore metabolite (BAY 1159184) are only available for the 0.4, 0.8, and 1.3 mg/kg dose cohorts. *Data are presented individually in the 0.2 mg/kg dose cohort due to the low number of patients with available pharmacokinetic data (n = 2)
Fig. 3
Fig. 3
Treatment duration in patients treated with aprutumab ixadotin. Dose reductions are indicated with a black arrow; dose reduction occurred a on day 22 from 0.8 to 0.4 mg/kg and b on day 23 from 1.3 to 0.8 mg/kg

References

    1. Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011;437(2):199–213. doi: 10.1042/bj20101603.
    1. De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal–epithelial signalling during mouse organogenesis. Development. 2000;127(3):483–492.
    1. Matsuda Y, Yoshimura H, Suzuki T, Uchida E, Naito Z, Ishiwata T. Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer. Cancer Sci. 2014;105(9):1212–1219. doi: 10.1111/cas.12470.
    1. Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clin Cancer Res. 1996;2(8):1373–1381.
    1. Carter EP, Fearon AE, Grose RP. Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends Cell Biol. 2015;25(4):221–233. doi: 10.1016/j.tcb.2014.11.003.
    1. Andre F, Cortes J. Rationale for targeting fibroblast growth factor receptor signaling in breast cancer. Breast Cancer Res Treat. 2015;150(1):1–8. doi: 10.1007/s10549-015-3301-y.
    1. Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61(5):673–684. doi: 10.1136/gutjnl-2011-301839.
    1. Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, Felip E, et al. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann Oncol. 2014;25(3):552–563. doi: 10.1093/annonc/mdt419.
    1. Kim S, Dubrovska A, Salamone RJ, Walker JR, Grandinetti KB, Bonamy GM, et al. FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells. PLoS One. 2013;8(1):e51671. doi: 10.1371/journal.pone.0051671.
    1. Martignetti JA, Camacho-Vanegas O, Priedigkeit N, Camacho C, Pereira E, Lin L, et al. Personalized ovarian cancer disease surveillance and detection of candidate therapeutic drug target in circulating tumor DNA. Neoplasia. 2014;16(1):97–103. doi: 10.1593/neo.131900.
    1. Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Natrajan R, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29(14):2013–2023. doi: 10.1038/onc.2009.489.
    1. Lee HJ, Kang HJ, Kim KM, Yu ES, Kim KH, Kim SM, et al. Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma. Clin Mol Hepatol. 2015;21(1):60–70. doi: 10.3350/cmh.2015.21.1.60.
    1. Matsuda Y, Ishiwata T, Yamahatsu K, Kawahara K, Hagio M, Peng WX, et al. Overexpressed fibroblast growth factor receptor 2 in the invasive front of colorectal cancer: a potential therapeutic target in colorectal cancer. Cancer Lett. 2011;309(2):209–219. doi: 10.1016/j.canlet.2011.06.009.
    1. Nomura S, Yoshitomi H, Takano S, Shida T, Kobayashi S, Ohtsuka M, et al. FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer. Br J Cancer. 2008;99(2):305–313. doi: 10.1038/sj.bjc.6604473.
    1. Ohashi R, Matsuda Y, Ishiwata T, Naito Z. Downregulation of fibroblast growth factor receptor 2 and its isoforms correlates with a high proliferation rate and poor prognosis in high-grade glioma. Oncol Rep. 2014;32(3):1163–1169. doi: 10.3892/or.2014.3283.
    1. Tokunaga R, Imamura Y, Nakamura K, Ishimoto T, Nakagawa S, Miyake K, et al. Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. Oncotarget. 2016;7(15):19748–19761. doi: 10.18632/oncotarget.7782.
    1. Parker BC, Engels M, Annala M, Zhang W. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J Pathol. 2014;232(1):4–15. doi: 10.1002/path.4297.
    1. Sievers EL, Senter PD. Antibody–drug conjugates in cancer therapy. Annu Rev Med. 2013;64:15–29. doi: 10.1146/annurev-med-050311-201823.
    1. Mack F, Ritchie M, Sapra P. The next generation of antibody drug conjugates. Semin Oncol. 2014;41(5):637–652. doi: 10.1053/j.seminoncol.2014.08.001.
    1. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov. 2017;16(5):315–337. doi: 10.1038/nrd.2016.268.
    1. Lambert JM, Morris CQ. Antibody-drug conjugates (ADCs) for personalized treatment of solid tumors: a review. Adv Ther. 2017;34(5):1015–1035. doi: 10.1007/s12325-017-0519-6.
    1. LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab emtansine: a unique antibody–drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 2011;17(20):6437–6447. doi: 10.1158/1078-0432.ccr-11-0762.
    1. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853–1862. doi: 10.1016/s0140-6736(15)60165-9.
    1. Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508–1516. doi: 10.1016/s0140-6736(12)60485-1.
    1. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–753. doi: 10.1056/NEJMoa1509277.
    1. Hedrich WD, Fandy TE, Ashour HM, Wang H, Hassan HE. Antibody-drug conjugates: pharmacokinetic/pharmacodynamic modeling, preclinical characterization, clinical studies, and lessons learned. Clin Pharmacokinet. 2018;57(6):687–703. doi: 10.1007/s40262-017-0619-0.
    1. Carter PJ, Lazar GA. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat Rev Drug Discov. 2018;17(3):197–223. doi: 10.1038/nrd.2017.227.
    1. Sommer A, Kopitz C, Schatz CA, Nising CF, Mahlert C, Lerchen HG, et al. Preclinical efficacy of the auristatin-based antibody–drug conjugate BAY 1187982 for the treatment of FGFR2-positive solid tumors. Cancer Res. 2016;76(21):6331–6339. doi: 10.1158/0008-5472.CAN-16-0180.
    1. Tibaldi C, Vasile E, Antonuzzo A, Di Marsico R, Fabbri A, Innocenti F, et al. First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study. Br J Cancer. 2008;98(3):558–563. doi: 10.1038/sj.bjc.6604187.
    1. Data on file, Bayer AG (2019)
    1. Wittemer-Rump S, Sommer A, Kopitz C, Huynh H, Schatz C, Zierz R, et al. Pharmacokinetic/pharmacodynamic (PK/PD) and toxicokinetic/toxicodynamic (TK/TD) modeling of preclinical data of FGFR2-ADC (BAY 1187982) to guide dosing in phase 1 [abstract]. In: Proceedings of the 106th annual meeting of the American Association for Cancer Research, 18–22 Apr 2015, Philadelphia, PA. Philadelphia, PA: AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1683. 10.1158/1538-7445.AM2015-1683
    1. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–2189. doi: 10.1200/jco.2011.38.0410.
    1. Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34(9):972–979. doi: 10.1200/jco.2015.64.0060.
    1. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–1496.
    1. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–1791. doi: 10.1056/NEJMoa1209124.
    1. Sexton DJ, Clarkson MR, Mazur MJ, Plant WD, Eustace JA. Serum D-dimer concentrations in nephrotic syndrome track with albuminuria, not estimated glomerular filtration rate. Am J Nephrol. 2012;36(6):554–560. doi: 10.1159/000345475.
    1. Mahmoodi BK, ten Kate MK, Waanders F, Veeger NJ, Brouwer JL, Vogt L, et al. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study. Circulation. 2008;117(2):224–230. doi: 10.1161/circulationaha.107.716951.
    1. Stagg NJ, Shen BQ, Brunstein F, Li C, Kamath AV, Zhong F, et al. Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: challenges and perspectives in translatability from nonclinical toxicology studies to the clinic. Regul Toxicol Pharmacol. 2016;82:1–13. doi: 10.1016/j.yrtph.2016.10.012.
    1. Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589–604. doi: 10.1089/jop.2015.0064.
    1. Younes A, Kim S, Romaguera J, Copeland A, Farial Sde C, Kwak LW, et al. Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2012;30(22):2776–2782. doi: 10.1200/jco.2011.39.4403.
    1. Tannir NM, Forero-Torres A, Ramchandren R, Pal SK, Ansell SM, Infante JR, et al. Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Investig New Drugs. 2014;32(6):1246–1257. doi: 10.1007/s10637-014-0151-0.
    1. Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, et al. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget. 2017;8(9):16052–16074. doi: 10.18632/oncotarget.14109.
    1. Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2017;35(2):157–165. doi: 10.1200/JCO.2016.67.2048.
    1. Paik PK, Shen R, Berger MF, Ferry D, Soria JC, Mathewson A, et al. A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers. Clin Cancer Res. 2017;23(18):5366–5373. doi: 10.1158/1078-0432.CCR-17-0645.
    1. Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21(12):2684–2694. doi: 10.1158/1078-0432.CCR-14-2329.
    1. Markham A. Erdafitinib: first global approval. Drugs. 2019;79(9):1017–1021. doi: 10.1007/s40265-019-01142-9.
    1. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody–drug conjugates. MAbs. 2016;8(4):659–671. doi: 10.1080/19420862.2016.1156829.
    1. Masters JC, Nickens DJ, Xuan D, Shazer RL, Amantea M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Investig New Drugs. 2018;36(1):121–135. doi: 10.1007/s10637-017-0520-6.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi