<div>Abstract<p><b>Background:</b> High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials.</p><p><b>Methods:</b> This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System.</p><p><b>Results:</b> Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (<i>P</i> = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (<i>P</i> < 0.0001): good prognosis [score 0–1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2–3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks).</p><p><b>Conclusion:</b> CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials. <i>Clin Cancer Res; 17(15); 5188–96. ©2011 AACR</i>.</p></div>
No description supplied
The performance of full-scale steel and composite bridge safety barriers under vehicle crash is evaluated by using the nonlinear explicit finite element code LS-DYNA. Two types of vehicles used in this study are passenger car and truck, and the performance criteria considered include structural strength and deformation, occupant protection, and post-crash vehicle behavior. It can be concluded that the composite safety barrier satisfies all performance criteria of vehicle crash. Although the steel safety barrier satisfies the performance criteria of occupant protection and post-crash vehicle behavior, it fails to satisfy the performance criterion of deformation. In all performance evaluations, the composite safety barrier exhibits a superior performance in comparing with the steel safety barrier.
2575 Background: Large sequencing studies in MCM have shown a TP53WT incidence of approximately 80%. In preclinical TP53WT melanoma models, the oral p53-MDM2 inhibitor AMG 232 exhibited synergistic, cytotoxic-type antitumor activity when combined with MAPK inhibitors. This phase 1 study assessed the toxicity (CTCAE 4.03), maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity (RECIST 1.1) of AMG 232 plus trametinib (T) and dabrafenib (D) (BRAF V600-mutant ) or T (BRAF V600-WT ) in pts with TP53WT MCM. Methods: Using 3+3 dose escalation design, pts with advanced TP53WT (using a CLIA-approved assay) MCM received AMG 232 PO QD for seven days of each 3-week cycle (7/21) at 120, 240, or 480 mg plus either T 2 mg PO QD and D 150 mg PO BID (Arm 1; BRAF V600-mutant ) or T 2 mg QD (Arm 2; BRAF nonV600-mutant ). Results: At the time of this analysis, 21 pts (median age, 58 y [range 24–76]; male, n = 11; at least 2 systemic treatments, n = 15) were treated. Arm 2 enrolled first: AMG 232 120 mg (n = 6), then 240 mg (n = 6). Due to chronic grade (G) 2 gastrointestinal toxicity, an intermediate dose (180 mg; n = 3) was determined as the preliminary MTD. Arm 1 enrolled at AMG 232 120 mg (n = 4), then 180 mg (n = 2). The most common reasons for AMG 232 withdrawal were disease progression (n = 8) and AEs (n = 4); 6 pts remain on AMG 232. All 21 pts had treatment-related AEs (TRAEs); the most common TRAEs were nausea (n = 18), fatigue (n = 17), diarrhea (n = 14), and vomiting (n = 13). The only DLT (Arm 2; 240 mg) was G 3 pulmonary embolism. Preliminary PK analysis suggests that AMG 232 exposure (area under the curve) is similar to that as monotherapy at the same dose, with no apparent drug-drug interaction between AMG 232 and T; analysis of D and T PK is ongoing. Of 21 pts, 6 had partial response (Arm 1/2, n = 4 [67%]/2 [13%]), 13 had stable disease (Arm 1/2, n = 2 [33%]/11 [73%]), and 2 progressed (Arm 1/2, n = 0/2 [13%]) as best response; 17 had tumor reduction (Arm 1/2, n = 6 [100%]/11 [73%]). Conclusions: In this population of pts with MCM, AMG 232 combined with D and/or T during DE was tolerable up to 180 mg QD 7/21 days, showing an acceptable PK profile and early antitumor activity. Clinical trial information: NCT02110355.
Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.
