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OBJECTIVE: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR). METHODS: Patients with measurable disease, acceptable organ function, performance status ≤2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of ≥40% with 90% power. RESULTS: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported. CONCLUSIONS: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615].

ObjectivesWhile Caucasian women are more likely to be diagnosed with endometrial cancer compared to African-American women, the rate of mortality is higher for African Americans. The cause of this disparity is unknown. We analyzed the time interval from diagnosis of endometrial cancer to treatment as it pertains to race and socioeconomic factors and its possible impact on survival.MethodsThis was a retrospective, single institution chart review using a cancer registry database. We identified 889 patients who were diagnosed with endometrial cancer between January 2005 and June 2012. Clinicopathologic characteristics, demographics, insurance status, distance from medical center, body mass index (BMI), dates of diagnosis, and treatment were obtained from the medical records. Survival and association was determined by a one-way ANOVA test.ResultsAt the time of the study, 699 patients were alive and 190 dead. The average age was noted to be 62 years (24–91 years). Stages I–IV disease accounted for 69, 6, 15, and 10%, respectively. White race accounted for 64%, African Americans 24%, and Hispanics 7% of our study population. Majority of patients were privately insured (n = 441) followed by Medicare (n = 375). The mean interval time from diagnosis to treatment was 47.5 days (0–363). A statistically significant difference was noted for this time interval with regard to both race and insurance status: white and African Americans (42.6 vs. 57.3 days, p = 0.048), privately insured and Medicare (38.4 vs. 54.1 days, p < 0.001). There was a significant association with increased risk of death with a longer delay (43.3 vs. 64.8 days, p < 0.001). No statistically significance was noted for distance from medical center or BMI.ConclusionA significant increase in interval of time from diagnosis to treatment of endometrial cancer was seen in both race and insurance status. A longer interval from diagnosis to treatment was associated mortality. The causes of these delays are likely multifactorial but deem further investigation given these data.

Purpose Effective treatments for advanced endometrial cancer are lacking. Novel therapies that target specific pathways hold promise for better treatment outcomes with less toxicity. Mutation activation of the FGFR2/RAS/ERK pathway is important in endometrial tumorigenesis. RPS6KA6 (Rsk4) is a putative tumor suppressor gene and is a target of the ERK signaling pathway. We explored the role of RSK4 in endometrial cancer. Experimental design We showed that RSK4 is expressed in normal endometrial tissue and is absent or much reduced in endometrial cancer. Based on previously reports on methylation in other cancers we hypothesized that the absence of RSK4 transcript is associated with epigenetic silencing rather than mutation. We determined the methylation and expression status of RSK4 in primary endometrial cancers and cell lines and the effects of treatment with a demethylating agent. The relationship between RSK4 methylation and clinicopathologic was assessed. Results RSK4 is frequently hypermethylated in endometrial cancer cells lines and in primary endometrial cancer compared to normal endometrial tissue. RSK4 methylation was significantly associated with tumor grade, with higher grade tumors having lower levels of methylation (p=0.03). RSK4 methylation levels were not associated with other clinical variables. We did find that RSK4 methylation was significantly correlated with expression in primary endometrial tumors and in cell lines. Re-activation of RSK4 by 5-azacytidine was successfully performed showing 8 to >1,200 fold increases in transcript levels. Conclusion RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation. Its role as suppressor in endometrial cancer, however, remains uncertain.