A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors
- 464 Downloads
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.
KeywordsNimotuzumab 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.
- 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
- 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
- 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.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.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.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.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
- 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.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.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.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.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.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.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
- 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
- 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