Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash☆
Introduction
Ovarian cancer is the leading cause of death among women with gynecologic malignancies. Ovarian cancer accounted for an estimated 22,430 new cases and 15,280 deaths in 2007 [1]. Epithelial ovarian cancer accounts for nearly 90% of all ovarian malignancies [2]. The standard therapy for advanced ovarian carcinoma is maximal cytoreductive surgery followed by platinum-based chemotherapy. In women treated with platinum-containing combinations as primary therapy, the response rates are 60–90%, with complete responses being most common in women who have optimal surgical cytoreduction. Despite these high response rates, most patients eventually die of disease persistence or recurrence, and long-term survival remains approximately 15–30% [2]. The addition of a third cytotoxic drug has not thus far resulted in increased survival [3]. Research is now focused on the evaluation of combining biologic agents with primary chemotherapy.
The epidermal growth factor (EGF) receptor (EGFR) is a member of the ERBB receptor tyrosine kinase family that consists of four structurally similar but functionally distinct membrane glycoproteins [4]. EGFR activation stimulates multiple cellular processes including cell cycle progression, inhibition of apoptosis, angiogenesis, tumor cell motility and metastasis [5]. Growth factors, such as the EGF and transforming growth factor-α, are potent mitogens for several human epithelial cell types including ovarian and have been implicated in cancer development and resistance to cisplatin [6], [7]. Thus, interruption of the mitogenic signaling pathways associated with EGFR tyrosine kinase is likely to inhibit cell proliferation of malignant tumors. EGFR expression in ovarian cancer is correlated with poor prognosis for patient survival making it a potential target in new regimens combining biologics and chemotherapy.
Cetuximab (Erbitux®, Bristol-Myers Squibb, New York, NY) is a chimeric monoclonal antibody which blocks the binding of EGF to its receptor, thus inhibiting ligand induced autophosphorylation of the receptor [8]. In addition, cetuximab leads to EGFR internalization effectively removing the receptor from the cell surface preventing further interaction with ligand. Cetuximab is now an integral part of the therapy in metastatic colorectal cancer (mCRC) and in advanced head and neck cancer [9], [10], [11].
The present study was conducted to determine the safety and efficacy of single agent cetuximab for the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma. An association between the development of an acneiform skin rash and response to cetuximab-containing therapy has been observed [12], [13], [14], [15]. Thus, this trial was designed with dose escalation to titrate dose to a grade 2 skin rash to assure delivery of sufficient drug to obtain a biological effect.
Section snippets
Patients
Women age 18 and older with a histologic diagnosis of persistent or recurrent epithelial ovarian carcinoma or primary peritoneal carcinoma were eligible for this trial. Patients' tumors had to demonstrate any degree of EGFR expression by immunohistochemistry using Dako kits (Dako North America, Carpinteria, CA) centrally performed by ImPATH Predictive Oncology (New York, NY). Patients were permitted to have up to two prior cytotoxic regimens and were required to have a platinum free interval of
Patient characteristics
Twenty-five patients were enrolled onto this study (Table 1), all of whom were EGFR positive. All were treated and included in the efficacy and safety analyses. Reasons for early discontinuation of study treatment included, study drug toxicity (1 patient), clinical deterioration without documented progression (1 patient) and ileus unrelated to cetuximab treatment (1 patient). These three patients received only the loading dose. Thus, there were 22 patients evaluable for response-dose escalation
Discussion
Cetuximab has become part of the standard of care in the treatment of mCRC and locally advanced and metastatic head and neck cancer [9], [10], [11]. Monoclonal antibodies against EGFR have a different spectrum of activity compared with small molecule tyrosine kinase inhibitors (TKIs) [25]. For example, monoclonal antibodies against EGFR are active in colon cancer while small molecule TKIs are not. We and others have shown that gefitinib and erlotinib were inactive in recurrent ovarian carcinoma
Conflict of interest statement
Russell J. Schilder–No conflict of interest.
Harsh B. Pathak–No conflict of interest.
Anna E. Lokshin–No conflict of interest.
Robert W. Holloway–No conflict of interest.
Ronald D. Alvarez–No conflict of interest.
Carol Aghajanian–No conflict of interest.
Hua Min–No conflict of interest.
Karthik Devarajan–No conflict of interest.
Eric Ross–No conflict of interest.
Charles W. Drescher–No conflict of interest.
Andrew K. Godwin–ImClone (research funding).
Acknowledgments
We thank Adele M. Marrangoni, Brian Nolen, Liudmila Velikokhatnaya, Matthew T. Winans, Denise Prosser, Dandan Chen for technical assistance and Dr. Kathleen Alpaugh for protocol support of the clinical trial.
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2017, Current Problems in CancerCitation Excerpt :In vitro, treating ovarian cancer cell lines with cetuximab inhibits cell growth, potentiates apoptosis, and impairs tumor metastasis.27 However, in a phase II trial of single-agent cetuximab in 25 patients with persistent or recurrent ovarian or primary peritoneal cancer, single patient achieved a partial response (PR), 9 patients had stable disease (SD), and median PFS was 21 months.28 A phase II study of EMD72000 (matuzumab), a humanized anti-EGFR mAb, of 37 heavily pretreated platinum-resistant patients did not yield any responses.28,29
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2016, Journal of Controlled ReleaseCitation Excerpt :Cetuximab binds to the extracellular domain of HER1 (human epidermal growth factor receptor 1) to avoid its ligand activation associated signaling and tumor growth (Fig. 2) [70]. Yet, it has not enough clinical value in patients of OC, either as single agent or in combination [71,72,73]. This might be because other signaling pathways (KRAS) can activate signaling for tumor growth when EGFR is blocked [74].
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The study was supported in part by Bristol-Myers Squibb Company, New York, New York, the Ovarian Cancer Research Fund, and the Ovarian Cancer SPORE at FCCC (P50 CA083638).