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

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Abstract

Objectives

Determine if cetuximab dose escalation to induce grade 2 rash correlates with anti-tumor activity and if sera-based markers could predict likelihood of response.

Methods

Patients with persistent/recurrent ovarian or primary peritoneal carcinoma received an initial dose of cetuximab 400 mg/m2, then 250 mg/m2 weekly for two 3-week cycles. Patients who had stable disease (SD) and < grade 2 rash were dose escalated in 75 mg/m2 increments every 3 weeks until grade 2 rash or to a maximum weekly dose of 400 mg/m2. Pre- and post-treatment serum samples were evaluated for potential predictive markers of response.

Results

One of 25 patients achieved partial remission (PR) and 9 patients had SD. The median progression free survival was 2.1 months; the 1-year survival rate was 54.8%. Rash (96%) was the most common drug-related adverse event. At first response assessment, 4 patients remained at 250 mg/m2; 8 patients were dose-escalated to 325 mg/m2; of these, 4 ultimately were increased to 400 mg/m2. Patients with progressive disease (PD) were removed from the study. Ninety-two serologic markers were analyzed from 20 patients to identify markers associated with clinical activity and/or predictive of outcome. Pretreatment levels of twelve markers were significantly elevated in patients exhibiting PD versus SD or PR; however, changes in marker levels during the course of treatment were not significant indicators of response.

Conclusions

Single-agent cetuximab showed minimal activity in patients with recurrent ovarian cancer. Patients with elevated levels of 12 serologic markers at baseline were more likely to have earlier disease progression.

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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    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).

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