A phase I clinical study of VB4-845: Weekly intratumoral administration of an anti-EpCAM recombinant fusion protein in patients with squamous cell carcinoma of the head and neck

VB4-845 is a scFv-Pseudomonas exotoxin A fusion construct that targets epithelial cell adhesion molecule (EpCAM). A phase I trial was conducted to determine the maximum tolerated dose (MTD) of VB4-845 when administered as weekly intratumoral (IT) injections to patients with squamous cell carcinoma of the head and neck (SCCHN). Secondary objectives included the evaluation of the safety, tolerability, pharmacokinetic profile, and immunogenicity, and a preliminary assessment of tumor response. Twenty patients with advanced, recurrent SCCHN were treated weekly for four weeks in ascending dose cohorts of 100, 200, 330, 500, 700, and 930 μg. The MTD was established as 930 μg with a dose limiting toxicity of elevated liver enzymes in two of five patients. VB4-845 therapy was well tolerated with common treatment-related adverse events of injection site reactions, fever, gastrointestinal disorders, and elevated liver enzyme levels. All patients developed antibodies to VB4-845 by the end of the study, but only seven patients had neutralizing antibodies. Preliminary efficacy data found 87.5% of EpCAM-positive patients had a positive response to VB4-845 therapy. Noninjected dermal metastases were also resolved in one patient. VB4-845 IT therapy is safe and feasible and warrants further clinical evaluation for the treatment of SCCHN.

[1]  L. Siu,et al.  Molecular targeted therapy of head and neck cancer: review and clinical development challenges. , 2007, European journal of cancer.

[2]  L. Licitra,et al.  Biological agents in head and neck cancer , 2007, Expert review of anticancer therapy.

[3]  W. Jerjes,et al.  The application of photodynamic therapy in the head and neck. , 2007, Dental update.

[4]  M. Posner.  Evolving strategies for combined-modality therapy for locally advanced head and neck cancer. , 2007, The oncologist.

[5]  G. Colucci,et al.  Cetuximab in squamous cell head and neck carcinomas. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  I. Pastan,et al.  Immunotoxin treatment of cancer. , 2007, Annual review of medicine.

[7]  A. Luebke,et al.  Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker , 2006, BMC Cancer.

[8]  Christopher U. Jones,et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. , 2006, The New England journal of medicine.

[9]  L. Wirth,et al.  Cetuximab and radiotherapy for head and neck cancer. , 2006, The New England journal of medicine.

[10]  R. Tishler,et al.  Integrating novel agents into the curative treatment of head and neck cancer , 2006, Expert review of anticancer therapy.

[11]  R. Stupp,et al.  A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy. , 2005, Clinical oncology (Royal College of Radiologists (Great Britain)).

[12]  W. Hong,et al.  Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  J. Baselga,et al.  Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  G. Macdonald,et al.  Effective tumor targeting: strategies for the delivery of Armed Antibodies. , 2005, Current opinion in drug discovery & development.

[15]  P. D. de Wilde,et al.  Intratumoral Administration of Recombinant Human Interleukin 12 in Head and Neck Squamous Cell Carcinoma Patients Elicits a T-Helper 1 Profile in the Locoregional Lymph Nodes , 2004, Clinical Cancer Research.

[16]  B. Groner,et al.  Regression of Cutaneous Tumor Lesions in Patients Intratumorally Injected with a Recombinant Single-chain Antibody-toxin Targeted to ErbB2/HER2 , 2003, Breast Cancer Research and Treatment.

[17]  I. Nagtegaal,et al.  The epithelial cell adhesion molecule (Ep-CAM) as a morphoregulatory molecule is a tool in surgical pathology. , 2003, The American journal of pathology.

[18]  M. Looman,et al.  Pharmacokinetics and immunological aspects of a phase Ib study with intratumoral administration of recombinant human interleukin-12 in patients with head and neck squamous cell carcinoma: a decrease of T-bet in peripheral blood mononuclear cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  A. Plückthun,et al.  A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  A. Gossmann,et al.  Superselectiye Embolization as Palliative Treatment of Recurrent Hemorrhage in Advanced Carcinoma of the Head and Neck , 2001 .

[21]  R H Wheeler,et al.  Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  A. Yoskovitch,et al.  Skin Metastases in Squamous Cell Carcinoma of the Head and Neck , 2001, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[23]  I. Pastan,et al.  Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  S. Litvinov,et al.  The biology of the 17–1A antigen (Ep-CAM) , 1999, Journal of Molecular Medicine.

[25]  J. Johnson,et al.  Skin metastases from head and neck squamous cell carcinoma: Incidence and impact , 1999, Head & neck.

[26]  J. V. van Krieken,et al.  Expression of Ep‐CAM in normal, regenerating, metaplastic, and neoplastic liver , 1999, The Journal of pathology.

[27]  H. A. Bakker,et al.  Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell–Cell Interactions Mediated by Classic Cadherins , 1997, The Journal of cell biology.

[28]  D. Liggitt,et al.  Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  H. A. Bakker,et al.  Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule , 1994, The Journal of cell biology.

[30]  A. Frankel.  Immunotoxin therapy of cancer. , 1993, Oncology.

[31]  I. Pastan,et al.  Targeted toxin therapy for the treatment of cancer. , 1989, Journal of the National Cancer Institute.

[32]  E. Schmelzer,et al.  EpCAM expression in normal, non-pathological tissues. , 2008, Frontiers in bioscience : a journal and virtual library.

[33]  F. Kloss,et al.  EpCAM expression in squamous cell carcinoma of the oral cavity: frequency and relationship to clinicopathologic features. , 2008, Oral oncology.

[34]  L. Scott,et al.  Cetuximab , 2012, Drugs.

[35]  G. Andry,et al.  Skin metastases from a head and neck carcinoma: a prognostic factor? , 2005, B-ENT.

[36]  A. Boudewyns,et al.  Management of stridor in neonates and infants. , 2005, B-ENT.

[37]  Alessandro Lugli,et al.  Frequent EpCam protein expression in human carcinomas. , 2004, Human pathology.

[38]  A. Gossmann,et al.  Superselective embolization as palliative treatment of recurrent hemorrhage in advanced carcinoma of the head and neck. , 2001, The Annals of otology, rhinology, and laryngology.

[39]  J. Perentesis,et al.  Protein toxin inhibitors of protein synthesis. , 1992, BioFactors.

[40]  D. Scheinberg,et al.  Monoclonal antibody therapy of cancer. , 1990, Cancer chemotherapy and biological response modifiers.