Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group Study.

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-alpha, or PDGFR-beta) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-beta 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.

A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group study.

BACKGROUND: Women who are genetically predisposed to ovarian cancer are at very high risk of developing this disease. Although risk-reducing salpingo-oophorectomy (RRSO) and various screening regimens are currently recommended to reduce ovarian cancer risk, the optimal management strategy has not been established nor have multiple additional issues been adequately addressed. We developed a collaboration among the Clinical Genetics Branch (National Cancer Institute's Intramural Research Program), the Gynecologic Oncology Group (GOG), and the Cancer Genetics Network to address these issues. METHODS: This is a prospective, international, two-cohort, nonrandomized study of women at genetic risk of ovarian cancer, who chose either to undergo RRSO or screening, at study enrollment. Primary study objectives include quantifying and comparing ovarian and breast cancer incidence in the two study groups, assessing feasibility and selected performance characteristics of a novel ovarian cancer screening strategy (the Risk of Ovarian Cancer Algorithm), evaluating various aspects of quality of life and nononcologic morbidity related to various interventions in at-risk women, and creating a biospecimen repository for subsequent translational research. RESULTS: Study accrual is complete as of November 2006; 2,605 participants enrolled: 1,030 (40%) into the surgical cohort and 1,575 (60%) into the screening cohort. Five years of prospective follow-up ends in November 2011. Verification of BRCA mutation carrier status is under way, either through patient-provided reports from clinical genetic testing done before enrollment or through research-based genetic testing being conducted as part of the protocol. Patient eligibility is currently under evaluation and baseline, surgical, pathology, and outcome data are still being collected. The study design and selected baseline characteristics of cohort members are summarized. CONCLUSION: This National Cancer Institute intramural/extramural collaboration will provide invaluable prospectively collected observational data on women at high familial ovarian cancer risk, including substantial numbers of women carrying BRCA1/2 mutations. These data will aid in elucidating the effect of RRSO on breast/ovarian cancer risk and the effects of two management strategies, on quality of life and other issues that may influence patient care, as well as providing preliminary estimates of test specificity and positive predictive value of a novel ovarian cancer screening strategy.

Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: a Gynecologic Oncology Group study.

PURPOSE: This phase II trial assessed the activity and tolerability of cetuximab (C225, Erbitux) in combination with carboplatin in patients with relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. PATIENTS AND METHODS: Patients were to receive combination therapy with cetuximab (initial dose of 400 mg/m2 intravenously on cycle 1, day 1, followed by weekly infusions of 250 mg/m2) and carboplatin (AUC of 6 on day 1 and every 3 weeks). The primary objectives of this trial were to estimate the anti-tumor activity and adverse events of this combination therapy. Immunohistochemical expression of EGFR was evaluated in tumor specimens from patients enrolled in this trial. RESULTS: Of the 29 patients, 28 (97%) were eligible and evaluable for analysis of the efficacy and toxicity of cetuximab administered in combination with carboplatin. Of the evaluable entries, 26 had EGFR-positive tumors and the response rate in this group of patients was as follows: 9 demonstrated an objective response (3 CR; 6 PR) and 8 had stable disease. The response rate did not meet criteria for opening a second stage of accrual. The median time to progression was 9.4+ months (range: .9-22.2+). The most commonly observed adverse events were dermatologic toxicity (grade 3 in 32%), thrombocytopenia (grade 3 in 14%), and hypersensitivity reactions (grade 3 and 4 in 18%). CONCLUSIONS: Cetuximab administered in combination with carboplatin had modest activity in screened patients with EGFR-positive, relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Cetuximab was associated with an acneiform rash in a majority of patients and occasional serious hypersensitivity reactions.