Phase II study of cetrorelix, a luteinizing hormone-releasing hormone antagonist in patients with platinum-resistant ovarian cancer

doi:10.1016/S0090-8258(03)00408-6

Gynecologic Oncology

Volume 90, Issue 3, September 2003, Pages 552-559

https://doi.org/10.1016/S0090-8258(03)00408-6 Get rights and content

Abstract

Objective

The goal of this work was to study the anticancer activity of cetrorelix, a decapeptide with LHRH receptor antagonist properties in patients with platinum-resistant ovarian cancer. About 80% of primary ovarian cancers and cell lines bear LHRH receptors. Cetrorelix has anticancer activity in in vitro and in vivo ovarian cancer models.

Methods

Eligible patients with ovarian or mullerian carcinoma resistant to platinum chemotherapy received cetrorelix 10 mg subcutaneously every day. Eligibility criteria included age ≥ 18, PS ≤ 2, measurable disease, chemistries and blood counts in normal range, no estrogen replacement for at least 2 weeks, and no known allergic reactions to extrinsic peptide. In patients volunteering for a biopsy, tissue was taken to perform a LHRH receptor assay.

Results

Seventeen patients were treated. Median age was 58 years. Median performance status was 0. Median number of prior chemotherapies was 3. Three patients had partial remissions lasting 9, 16, and 17 weeks. Toxicities effects included grade 4 anaphylactoid reaction (one patient) controlled by cortisol and cimetidine, grade 2 histamine reaction (two patients), grade 2 arthralgia (one patient) 20% cholesterol increase (two patients, who did not require specific treatment), minor hot flushes, headache, and local skin reaction at the injection site. Six of seven samples were LHRH receptor positive for mRNA and/or ligand assay. Two responding patients were LHRH receptor positive. The patient who had no receptor did not respond.

Conclusion

Cetrorelix has activity against ovarian cancer in this refractory population, and has minimal toxicity, except for potential anaphylactoid reactions. Activity may be mediated through the LHRH receptor.

Introduction

Ovarian cancer is the leading cause of death from gynecologic cancer. Most patients are diagnosed at an advanced stage. Although first-line treatment yields about 30% complete pathologic remission and an overall response rate of 75%, the disease usually recurs, and less than 25% of patients are alive at 5 years [1]. Chemotherapy and radical surgery have been the most powerful tools that may lead to cure, but if the cancer recurs, chemotherapy becomes palliative. Current focus of research is to better understand the biology of cancers, to inhibit the pathways that lead to uncontrolled cell growth [2].

The ovaries are the reservoir of female sexual steroids, and during the active sexual period, they are under the control of the hypothalamic pituitary gonadal axis. They are therefore an endocrine gland. Epithelial ovarian cancer originates in the epithelial monocellular layer that covers the ovaries. Luteinizing hormone-releasing hormone receptors have been found in these cells and their activation affects cell proliferation [3]. Previous clinical studies of hormonal agents in patients with refractory ovarian cancer report response rates between 10 and 15%, and stabilization of disease in 30%. Most trials have studied progestagens, antiestrogens, and LHRH agonists [4], [5].

Cetrorelix, a pure LHRH antagonist, was discovered by Dr. Schally. Cetrorelix blocks the gonadotropin-releasing hormone receptor in the pituitary gland and therefore, immediately blocks the gonadotropic axis by preventing the release of LH and FSH [6]. Cetrorelix has also been shown to have direct effects through an LHRH receptor on a wide range of endocrine and other cells [7], [8], [9]. Eighty percent of ovarian cancers bear LHRH receptors [10]. Cetrorelix is currently approved in Germany for ovulation induction in women with infertility problems. Because of in vitro and animal studies demonstrating the activity of cetrorelix against ovarian cancer xenografts and cell cultures [11], [12] we sought to study the anticancer potential of cetrorelix in women with platinum-resistant epithelial ovarian carcinoma. The objectives of this study were (1) to determine the efficacy of cetrorelix in patients with platinum-resistant ovarian carcinoma by evaluating the response rate and its duration, as well as overall patient survival; (2) to establish the safety of daily administration of cetrorelix by identifying the objective and subjective adverse events, and their reversibility, associated with treatment in this patient population; (3) to study the pharmacologic and endocrinologic effects of five different doses and two different concentrated forms of cetrorelix; and (4) to gather information on the cellular and molecular biology of ovarian cancer treated with cetrorelix.

Section snippets

Patients and methods

This phase II trial was a two-center study centralized from the University of Texas M.D. Anderson Cancer Center (MDACC). The trial was performed at MDACC and at the University of Marburg in Germany. The study was approved by the institutional review boards of both hospitals. Each patient signed an informed consent before participation in this clinical study.

Results

Nineteen patients with platinum-resistant ovarian cancer were enrolled in the study between February 1996 and April 1998. Of the 19 patients registered, 17 patients were evaluable for both toxicity and response, and 2 patients were never treated because of intercurrent illnesses.

The characteristics of the 17 treated patients are listed in Table 2. The median age was 58 years (range, 46–76 years). The median Zubrod performance status was 0 (range, 0–1). All patients had prior surgery and

Discussion

Of 17 patients with ovarian cancer treated with cetrorelix, 3 obtained a partial remission (18%), which lasted 9 to 17 weeks. Furthermore, 6 patients experienced disease stabilization (35%) for up to 62 months. In this very refractory patient population, these results are interesting, when compared with palliative chemotherapy, which induces similar duration of remission and overall survival [16].

Except for rare anaphylactoid reactions related to histamine release, the toxicity of cetrorelix

Acknowledgements

We thank Dr. Michael Bevers and Dr. Creighton Edwards for their surgical expertise.

This work was supported by ASTA Medica, Inc., and NIH Grant R21-CA-72004-02

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Regular articlePhase II study of cetrorelix, a luteinizing hormone-releasing hormone antagonist in patients with platinum-resistant ovarian cancer

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Hematol Oncol Clin North Am

Controlled Clin Trials

Gynecol Oncol

Fertil Steril

Urology

Eur J Cancer

J Urol

The epidemiology of epithelial ovarian cancera review

Int J Gynecol Cancer

Role of gonadotropin-releasing hormone as an autocrine growth factor in human ovarian surface epithelium

Endocrinology

Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects

Proc Natl Acad Sci USA

Actions of gonadotropin-releasing hormone antagonists on steroidogenesis in human granulosa lutein cells

Eur J Endocrinol

Regular article
Phase II study of cetrorelix, a luteinizing hormone-releasing hormone antagonist in patients with platinum-resistant ovarian cancer