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The acquisition of American English /r/ is of particular theoretical and clinical interest because it is typologically rare among the world’s languages, because it is one of the latest-acquired sounds by typically developing children, and because it is one of the sounds that is most likely produced in error by children with residual speech sound disorders. In this study, we examined the accuracy productions of /r/ and its most frequent substitute, /w/, by preschool children (n = 120) at two time-points: when they were between 3;3 (years;months) and 4;4 years old and again when they were 4;4 to 5;4 years. Accuracy was determined both by trained phonetic transcriber. Moreover, the accuracy of productions from the first time-point was rated by groups of naive listeners using a perceptual rating experiment similar to that described by Schellinger et al. (2016). Considerable variation in /r/ production was found at both time-points, and there was sizeable variation in the extent to which production improved fr...

e12019 Background: SU, an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET has activity in heavily pretreated pts with MBC. The aromatase inhibitor (AI), E, has proven 1st-line activity that compares favorably with tamoxifen in pts with HR+ BC in the adjuvant setting (Jones et al. 2008). Combining agents that target different signaling pathways may have additive/synergistic activity; combining the AI letrozole with the anti-VEGF agent bevacizumab prolonged progression-free survival to >14 mos as 1st-line therapy for HR+ MBC (Dickler et al. 2008). An open-label, phase I, dose-finding study of first-line SU + E was conducted in HR+ MBC pts. Methods: Eligible pts (postmenopausal; female; ≥18 yrs) had an ECOG PS ≤1, LVEF ≥50% and locally recurrent (unresectable) or MBC. Exclusion criteria included HER2+ BC (unless pt had progressed after trastuzumab) and prior treatment in the metastatic setting. Pts received SU 37.5 mg/d + E 25 mg/d on a continuous daily dosing regimen; if dose-limiting toxicities (DLTs) were experienced by >1/6 pts in the first 8 wks then further pts would be enrolled at SU 25 mg/d + E 25 mg/d. Pharmacokinetic (PK) analyses were performed for each drug and the active SU metabolite SU12662. Results: As of December 2008, enrollment was completed (N=6; mean age 59 ± 11 yrs; 50% of pts had ≥3 metastatic sites). No DLTs were observed and no dose reductions were required throughout the treatment period. An overview of key data is shown below. One death occurred on study (non treatment-related Enterobacter sepsis). No treatment-related G4/5 AEs occurred. PK parameter values determined for SU and E suggested increases in the systemic exposure of both drugs when administered concurrently. Conclusions: These data indicate that SU + E was tolerable with manageable toxicities, with increases in PK parameters and a similar AE profile to that of either single agent alone. This combination should be considered in future clinical trials. [Table: see text] [Table: see text]