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The Global ETD Search service is a free service for researchers
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Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
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Showing 1 to 7 of 7 (0.074 seconds)Spelling suggestions: "subject:"aximum tolerated dose"" "subject:"aximum tolerated pose""
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Statistical design of phase I clinical trialsZhang, Weijia 16 September 2016 (has links)
My MSc thesis is focused on parametric designs of Phase I clinical trials, using the continual reassessment method. A parametric model with unknown parameters is assumed. The observations are either toxic or nontoxic. Observations of toxicities are used to update the posterior distribution. Dose selection for the next patient is based on the estimated toxicity probability. The objective is to identify the maximum tolerated dose to be used in Phase II clinical trials. We introduce a new class of parametric functions for the continual reassessment method. This class is formed with the cumulative distribution function of the normal distribution. The major advantage is that we can choose different normal distributions to model different toxicity probability functions. We conduct simulation studies and compare our new design with the existing parametric designs, and have found that our design performs better by choosing the appropriate values of the mean and variance. / October 2016
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Safety limit estimation for cataract induced by ultraviolet radiation /Dong, Xiuqin, January 2005 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.
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Dose-Response Analysis for Time-Dependent EfficacyIslam, Mohammad Mafijul 18 July 2016 (has links)
No description available.
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Estudo do impacto da escolha do modelo para o controle de overdose na fase I dos ensaios clínicos / Study of the impact of model choice for overdose control in phase I of clinical trialsMarins, Bruna Aparecida Barbosa 03 October 2018 (has links)
Escalonamento com controle de overdose (EWOC-PH, escalation with overdose control proporcional hazards) é um método bayesiano com controle de overdose que estima a dose máxima tolerada (MTD, maximum tolerated dose) assumindo que o tempo que um paciente leva para apresentar toxicidade segue o modelo de riscos proporcionais. Neste trabalho analisamos quais são as consequências em adotarmos um método que se baseia no modelo de riscos proporcionais quando o tempo até toxicidade segue o modelo de chances de sobrevivência proporcionais. A fim de buscar responder se teríamos uma superestimativa ou uma subestimativa da MTD foram feitas simulações em que consideramos dados de chances de sobrevivência proporcionais e aplicação do método EWOC-PH para analisarmos a MTD. Como uma extensão do método EWOC-PH, propomos o método EWOC-POS que assume que os tempos seguem o modelo de chances de sobrevivência proporcionais. / Escalation with overdose control proportional hazards is a Bayesian method with overdose control that estimates the maximum tolerated dose (MTD) assuming that the time a patient takes to show toxicity follows the proportional hazards model. In this work, we analyse the consequences of adopting a method based on the proportional hazard model when the time until toxicity follows the proportional survival model. In order to seek to answer if we would have an overestimate or an underestimate of MTD, simulations were performed in which we considered proportional odds survival data and application of the EWOC-PH method. As an extension of the EWOC-PH method, we propose the EWOC-POS method which assumes that time until toxicity follows the proportional odds survival model.
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Advanced Designs of Cancer Phase I and Phase II Clinical TrialsCui, Ye 13 May 2013 (has links)
The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.
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Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumorsHochhauser, D., Meyer, T., Spanswick, V.J., Wu, J., Clingen, P.H., Loadman, Paul, Cobb, M., Gumbrell, L., Begent, R.H., Hartley, J.A., Jodrell, D. January 2009 (has links)
No / PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
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Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladderSutherland, Mark, Gill, Jason H., Loadman, Paul, Laye, Jonathan P., Sheldrake, Helen M., Illingworth, Nicola A., Alandas, Mohammed N., Cooper, Patricia A., Searcey, M., Pors, Klaus, Shnyder, Steven, Patterson, Laurence H. 01 October 2012 (has links)
No / We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.
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