Summary
Nimotuzumab (h-R3) is a humanized anti-epidermal growth factor receptor monoclonal antibody. We conducted a phase I study to assess the safety, tolerance, maximal tolerance dose (MTD) and efficacy of h-R3 in combination with concurrent chemoradiation in patient with locally advanced esophageal carcinoma. Patients with locally advanced squamous cell carcinoma of esophagus were eligible. A total dose of 61.2 Gy was delivered by conventional fractionation. Chemotherapy was concurrently administered with irradiation every 4 weeks with PF regimen (cis-platinum of 25 mg/m2/d, d1-3; 5-Fu of 1,800 mg/m2, intravenously infusion in 72 h) for 4 cycles. h-R3 was administrated weekly during irradiation for 6 weeks. h-R3 dose escalation started with 100 mg/week, and followed by 200 mg/week and 400 mg/week. Three patients were enrolled in of each dose cohort. 11 patients were enrolled in the trial with 3, 4 and 4 in 100 mg/week, 200 mg/week and 400 mg/week cohort, respectively. 2 patients in 200 mg/week and 400 mg/week cohort were withdrawn due to patients’ own decisions. No dose limiting toxicity was observed. Grade 3–4 of esophagitis, Grade 3 of leucocytopenia and neutrocytopenia occurred in 18% (2/11), 18% (2/11) and 9% (1/11) of patients, respectively. For nimotuzumab-related toxicity only one patient experienced Grade 1 skin rash, and no Grade ≥3 of toxicity was noticed. In 9 patients, who completed planned treatments, 6-month and 1-year overall survival were 78% and 67%, respectively, and 1 year local progression-free survival, 100%. h-R3 of 400 mg/week administered concurrently with chemoradiation was well-tolerant. MTD has not been reached yet.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90
Mariotto A, Gigli A, Capocaccia R, Tavilla A, Clegg LX, Depry M, Scoppa S, Ries LAG, Rowland JH, Tesauro G, Feuer EJ (2002) SEER cancer statistics review, 1973–1999. Bethesda, MD: National Cancer Institute http://seer.cancer.gov/csr/1973_1999/prevalence.pdf
Dragovich T, Campen C (2009) Anti-EGFR-targeted therapy for esophageal and gastric cancers: an evolving concept. J Oncol 2009:1–8
Crombet-Ramos 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 101:567–575
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(4):749–755
Rodríguez MO, Rivero TC, del Castillo Bahi R, Muchuli CR, Bilbao MA, Vinageras EN, Alert J, Galainena JJ, Rodríguez E, Gracias E, Mulén B, Wilkinson B, de 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):343–349
Ramakrishnan MS, Eswaraiah A, Crombet T, Piedra P, Saurez G, Lyer H, Arvind AS (2009) Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs 1(1):41–48
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL (1999) Chemoradiation of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 281(17):1623–1627
Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP (2002) INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 20(5):1167–1174
You B, Brade A, Magalhaes JM, Siu LL, Oza A, Lovell S, Wang L, Hedley DW, Nicacio LV, Chen EX (2010) 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, May 8. [Epub ahead of print]
Crombet T, Torres L, Neninger E, Catalá 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, in patients with advanced epithelial-derived cancer. J Immunother 26(2):139–148
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11(1):21–28
Huang XD, Xu GZ, Gao L (2007) Combined therapy of irradiation and Nimotuzumab for nasopharyngeal carcinoma. Chin J Oncol 29:197–201
Crombet T, Osorio M, Cruz T, Roca C, del Castillo R, Mon R, Iznaga-Escobar N, Figueredo R, Koropatnick J, Renginfo E, Fernández E, Alvárez 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):1646–1654
Ramos TC, 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):375–379
Harari PM (2004) Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer 11(4):689–708
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):373–382
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):2474–2482
Acknowledgement
This study was financially supported by a grant from Ministry of Health, People’s Republic of China (Wei Guicai 2010 439).
Conflict of interest statement
No interest conflict except that the studied drug, r-R3 was donated by Biotech Pharma Com., Beijing, China
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhao, Kl., Hu, Xc., Wu, Xh. et al. A phase I dose escalation study of Nimotuzumab in combination with concurrent chemoradiation for patients with locally advanced squamous cell carcinoma of esophagus. Invest New Drugs 30, 1585–1590 (2012). https://doi.org/10.1007/s10637-011-9735-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-011-9735-0