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PURPOSE: Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors. PATIENTS AND METHODS: We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily. RESULTS: Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles. CONCLUSION: The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.

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PURPOSE: Long wait times are a primary source of dissatisfaction among patients enrolled in early-phase clinical trials. We hypothesized that an automated patient check-in system with readily available display for increasing awareness of waiting intervals would improve patient flow and use of our rooms, with decreased turnover time and increased throughput. METHODS: We recorded in-room wait times for patients seen in our clinic and observed the logistics involved in the blood collection process to delineate causes for delays. We then implemented a three-step strategy to alleviate the causes of these delays: (1) changing the collection of materials and the review of faxed orders, (2) improving our LabTracker automated database system that included wait time calculators and real-time information regarding patient status, and (3) streamlining lower complexity appointments. RESULTS: After our intervention, we observed a 19% decrease in mean wait times and a 30% decrease in wait times among patients waiting the longest (95th percentile). We also observed an increase in staff productivity during this process. Modifications in LabTracker provided the biggest reduction in mean wait times (17%). CONCLUSION: We observed a significant decrease in mean wait times after implementing our intervention. This decrease led to increased staff productivity and cost savings. Once wait times became a measurable metric, we were able to identify causes for delays and improve our operations, which can be performed in any patient care facility.

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Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm.

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