Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 5, pp 1063–1071 | Cite as

A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors

  • Wataru OkamotoEmail author
  • Takayuki Yoshino
  • Toshiaki Takahashi
  • Isamu Okamoto
  • Shinya Ueda
  • Asuka Tsuya
  • Narikazu Boku
  • Kazuto Nishio
  • Masahiro Fukuoka
  • Nobuyuki Yamamoto
  • Kazuhiko Nakagawa
Original Article



Nimotuzumab is a humanized IgG1 monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors.


Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens.


Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression.


Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.


Nimotuzumab EGFR Phase 1 Pharmacokinetics Solid tumor 



The authors would like to thank all the patients who participated in this study as well as Hiroshi Terakawa, Kenji Hirotani, Yuko Aramaki, Kiyo Nishimoto, Taiga Takagi and Koji Ishizuka in DAIICHI SANKYO CO., LTD. (Tokyo, Japan) for the assistance. This study was supported by DAIICHI SANKYO CO., LTD. which provided study medication and assistance with data collection.

Conflict of interest

Wataru Okamoto, Takayuki Yoshino, Toshiaki Takahashi, Isamu Okamoto, Shinya Ueda, Asuka Tsuya, Narikazu Boku, Kazuto Nishio, Masahiro Fukuoka, Nobuyuki Yamamoto, and Kazuhiko Nakagawa received a research funding for conducting this study from DAIICHI SANKYO CO., LTD. Masahiro Fukuoka and Narikazu Boku received lecture fees from DAIICHI SANKYO CO., LTD.

Supplementary material

280_2013_2277_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 28 kb)


  1. 1.
    Pal SK, Pegram M (2005) Epidermal growth factor receptor and signal transduction: potential targets for anti-cancer therapy. Anticancer Drugs 16:483–494PubMedCrossRefGoogle Scholar
  2. 2.
    Rivera F, Vega-Villegas ME, Lopez-Brea MF, Marquez R (2008) Current situation of panitumumab, matuzumab, nimotuzumab and zalutumumab. Acta Oncol 47:9–19PubMedCrossRefGoogle Scholar
  3. 3.
    Shawnta C, Aminah J (2010) STEPP for the EGFR inhibitor–induced rash—definitely a step in the right direction. Curr Oncol Rep 12:223–225CrossRefGoogle Scholar
  4. 4.
    Racca P, Fanchini L, Caliendo V, Ritorto G, Evangelista W, Volpatto R, Milanesi E, Ciorba A, Paris M, Facilissimo I, Macripò G, Clerico M, Ciuffreda L (2008) Efficacy and skin toxicity management with cetuximab in metastatic colorectal cancer: outcomes from an oncologic/dermatologic cooperation. Clin Colorectal Cancer 7(1):48–54PubMedCrossRefGoogle Scholar
  5. 5.
    Pinto C, Barone CA, Girolomoni G, Russi EG, Merlano MC, Ferrari D, Maiello E (2011) Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. Oncologist 16:228–238PubMedCrossRefGoogle Scholar
  6. 6.
    Crombet T, Rak J, Pérez R, Viloria-Petit A (2002) Antiproliferative, antiangiogenic, and proapoptotic activity of H-R3: a humanized anti-EGFR antibody. Int J Cancer 101:567–575CrossRefGoogle Scholar
  7. 7.
    Maceira M, Rengifo E, Cedeño M, Merino N, Parada AC (2004) Immunohistochemical recognition of the epidermal growth factor receptor by the h-R3 antibody in the skin of experimental animals. Appl Immunohistochem Mol Morphol 12(4):360–363PubMedCrossRefGoogle Scholar
  8. 8.
    Akashi Y, Okamoto I, Iwasa T, Yoshida T, Suzuki M, Hatashita E, Yamada Y, Satoh T, Fukuoka M, Ono K, Nakagawa K (2008) Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 98:749–755PubMedCrossRefGoogle Scholar
  9. 9.
    Basavaraj C, Sierra P, Shivu J, Melarkode R, Montero E, Nair P (2010) Nimotuzumab with chemoradiation confers survival advantage in treatment naïve head and neck tumors overexpressing EGFR. Cancer Biol Ther 10(7):673–681PubMedCrossRefGoogle Scholar
  10. 10.
    Rojo F, Gracias E, Villena N, Cruz T, Corominas JM, Corradino I, Cedeño M, Campas C, Osorio M, Iznaga N, Bellosillo B, Rovira A, Marsoni S, Gascon P, Serrano S, Sessa C, Crombet T, Albanell J (2010) Pharmacodynamic trial of nimotuzumab in unresectable squamous cell carcinoma of the head and neck: a SENDO foundation study. Clin Cancer Res 16(8):2474–2482PubMedCrossRefGoogle Scholar
  11. 11.
    Crombet T, Osorio M, Cruz T, Roca C, Castillo R, Mon R, Iznaga-Escobar N, Figueredo R, Koropatnick J, Renginfo E, Ferna’ndez E, Alva’rez D, Torres O, Ramos M, Leonard I, Pérez R, Lage A (2004) Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 22(9):1646–1654PubMedCrossRefGoogle Scholar
  12. 12.
    Rodríguez MO, Rivero TC, Bahi RC, Muchuli CR, Bilbao MA, Vinageras EN, Alert J, Galainena JJ, Rodríguez E, Gracias E, Mulén B, Wilkinson B, Armas EL, Pérez K, Pineda I, Frómeta M, Leonard I, Mullens V, Viada C, Luaces P, Torres O, Iznaga N, Crombet T (2010) Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck cancer. Biol Ther 9(5):343–349CrossRefGoogle Scholar
  13. 13.
    Crombet T, Figueredo J, Catala M, González S, Selva JC, Cruz TM, Toledo C, Silva S, Pestano Y, Ramos M, Leonard I, Torres O, Marinello P, Pérez R, Lage A (2006) Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3. Cancer Biol Ther 5(4):375–379CrossRefGoogle Scholar
  14. 14.
    Talavera A, Friemann R, Gómez-Puerta S, Martinez-Fleites C, Garrido G, Rabasa A, López-Requena A, Pupo A, Johansen RF, Sa’nchez O, Krengel U, Morenoet E (2009) Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. Cancer Res 69(14):5851–5859PubMedCrossRefGoogle Scholar
  15. 15.
    Garrido G, Tikhomirov IA, Rabasa A, Yang E, Gracia E, Iznaga N, Fernández LE, Crombet T, Kerbel RS, Pérez R (2011) Bivalent binding by intermediate affinity of nimotuzumab: a contribution to explain antibody clinical profile. Cancer Biol Ther 11(4):373–382PubMedCrossRefGoogle Scholar
  16. 16.
    You B, Brade A, Magalhaes JM, Siu LL, Oza A, Lovell S, Wang L, Hedley DW, Nicacio LV, Chen EX (2011) A dose-escalation phase I trial of nimotuzumab, an antibody against the epidermal growth factor receptor, in patients with advanced solid malignancies. Invest New Drugs 29(5):996–1003PubMedCrossRefGoogle Scholar
  17. 17.
    Crombet T, Torres L, Neninger E, Catala’ M, Solano ME, Perera A, Torres O, Iznaga N, Torres F, Pérez R, Lage A (2003) Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, patients with advanced epithelial-derived cancer. J Immunother 26(2):139–148PubMedCrossRefGoogle Scholar
  18. 18.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, Ludovini V, Magrini E, Gregorc V, Doglioni C, Sidoni A, Tonato M, Franklin WA, Crino L, Bunn PA Jr, Varella-Garcia M (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non–small-cell lung cancer. Nat Cancer Inst 97(9):643–655CrossRefGoogle Scholar
  19. 19.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, Santos GC, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353(2):133–144PubMedCrossRefGoogle Scholar
  20. 20.
    Kim YH, Sasaki Y, Lee KH, Rha SY, Park S, Boku N, Komatsu Y, Kim T, Kim S, Sakata Y (2011) Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil-based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: preliminary results. ASCO GI poster session abstract 87Google Scholar
  21. 21.
    Knijn N, Tol J, Koopman M, Werter MJBP, Imholz ALT, Valster FAA, Mol L, Vincent AD, Teerenstra S, Punt CJA (2011) The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatin-based systemic treatment in advanced colorectal cancer patients. Eur J Cancer 47:369–374PubMedCrossRefGoogle Scholar
  22. 22.
    Bodnar L, Wcislo G, Gasowska-Bodnar A, Synowiec A, Szarlej-Wcisło K, Szczylika C (2008) Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study. Eur J Cancer 44:2608–2614PubMedCrossRefGoogle Scholar
  23. 23.
    Cao Y, Liao C, Tan A, Liu L, Gao F (2010) Meta-analysis of incidence and risk of hypomagnesemia with cetuximab for advanced cancer. Chemotherapy 56:459–465PubMedCrossRefGoogle Scholar
  24. 24.
    Fernandez A, Spitzer E, Perez R, Boehmer FD, Eckert K, Zschiesche W, Grosse R (1992) A new monoclonal antibody for detection of EGF-receptors in western blots and paraffin-embedded tissue sections. J Cel Biochem 49(2):157–165CrossRefGoogle Scholar
  25. 25.
    Hirsch FR, Herbst RS, Olsen C, Chansky K, Crowley J, Kelly K, Franklin WA, Bunn PA Jr, Varella-Garcia M, Gandara DR (2008) Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non–small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 26(20):3351–3357PubMedCrossRefGoogle Scholar
  26. 26.
    Boland WK, Bebb G (2009) Nimotuzumab: a novel anti-EGFR monoclonal antibody that retains anti-EGFR activity while minimizing skin toxicity. Expert Opin Biol Ther 9(9):1–7CrossRefGoogle Scholar
  27. 27.
    Kimura M, Tsuda H, Morita D, Ichikura T, Ogata S, Aida S, Yoshizumi Y, Maehara T, Mochizuki H, Matsubara O (2004) A proposal for diagnostically meaningful criteria to classify increased epidermal growth factor receptor and c-erbB-2 gene copy numbers in gastric carcinoma, based on correlation of fluorescence in situ hybridization and immunohistochemical measurements. Virchows Arch 445(3):255–262PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Wataru Okamoto
    • 1
    Email author
  • Takayuki Yoshino
    • 2
  • Toshiaki Takahashi
    • 3
  • Isamu Okamoto
    • 1
  • Shinya Ueda
    • 1
  • Asuka Tsuya
    • 3
  • Narikazu Boku
    • 2
  • Kazuto Nishio
    • 4
  • Masahiro Fukuoka
    • 1
  • Nobuyuki Yamamoto
    • 3
  • Kazuhiko Nakagawa
    • 1
  1. 1.Department of Medical OncologyKinki University Faculty of MedicineOsakaJapan
  2. 2.Division of Gastrointestinal OncologyShizuoka Cancer CenterShizuokaJapan
  3. 3.Division of Thoracic OncologyShizuoka Cancer CenterShizuokaJapan
  4. 4.Department of Genome BiologyKinki University Faculty of MedicineOsakaJapan

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