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Phase II Evaluation of Imatinib Mesylate in the Treatment of Recurrent or Persistent Epithelial Ovarian or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study

Russell J. Schilder, Michael W. Sill, Roger B. Lee, Tanya J. Shaw, Mary K. Senterman, Andres J. Klein-Szanto, Zoe Miner, Barbara C. Vanderhyden

From the Fox Chase Cancer Center, Philadelphia, PA; Gynecologic Oncology Group Statistical and Data Center; University at Buffalo, Buffalo, NY; Tacoma General Hospital, Tacoma, WA; University of Ottawa, Ottawa, Ontario, Canada; Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada

Corresponding author: Russell J. Schilder, MD, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111; e-mail: russell.schilder{at}fccc.edu

Purpose This phase II trial assessed the activity and tolerability of an oral dose of imatinib mesylate 400 mg twice daily in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. The association between the expression of certain markers and clinical outcome was investigated.

Patients and Methods Primary measure of clinical efficacy was progression-free survival (PFS) at 6 months. Mutational analysis of KIT, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay for markers (KIT, platelet-derived growth factor [PDGF] receptor [-R], AKT2, phosphorylated AKT [p-AKT], stem cell factor [SCF], and PDGF) were performed.

Results Fifty-six eligible patients were evaluated. Nine patients were progression free for at least 6 months including one complete responder. The median PFS and survival were 2 and 16 months, respectively. The most common grade 3 and 4 toxicities were neutropenia, GI, dermatologic effects, pain, and electrolyte disturbances. At least one target of imatinib (KIT, PDGFR-, or PDGFR-β) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-β were associated with shorter PFS, and higher IHC scores (% immunopositive cells x staining intensity) of SCF and p-AKT were associated with decreased overall survival. No sequence mutations were detected in the KIT gene. Higher pretreatment plasma concentrations of PDGF-AB, PDGF-BB, and vascular endothelial growth factor (VEGF) were individually associated with shorter PFS and survival.

Conclusion Imatinib mesylate was well tolerated but had minimal single-agent activity in patients with recurrent ovarian or primary peritoneal carcinoma. No marker was identified that would predict activity of imatinib; however, tumor p-AKT and plasma VEGF levels were associated with poor outcome.

Supported by National Cancer Institute Grants No. CA27469 (Gynecologic Oncology Group) and CA37517 (Gynecologic Oncology Group Statistical and Data Center). The translational research elements of this study were supported in part by the National Cancer Institute of Canada, with funds from the Terry Fox Foundation (B.C.V.) and the Betty Irene West Doctoral Research Scholarship from the Canadian Institutes of Health Research (T.J.S.), and by the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Ovarian Cancer awarded to Fox Chase Cancer Center (Grant No. CA83638).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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