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Novel Designs Of Early Phase Trials For Cancer Therapeutics

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Novel Designs of Early Phase Trials for Cancer Therapeutics

Novel Designs of Early Phase Trials for Cancer Therapeutics Book
Author : Shivaani Kummar,Chris Takimoto
Publisher : Academic Press
Release : 2018-05-22
ISBN : 0128125705
Language : En, Es, Fr & De

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Book Description :

Novel Designs of Early Phase Trials for Cancer Therapeutics provides a comprehensive review by leaders in the field of the process of drug development, the integration of molecular profiling, the changes in early phase trial designs, and endpoints to optimally develop a new generation of cancer therapeutics. The book discusses topics such as statistical perspectives on cohort expansions, the role and application of molecular profiling and how to integrate biomarkers in early phase trials. Additionally, it discusses how to incorporate patient reported outcomes in phase one trials. This book is a valuable resource for medical oncologists, basic and translational biomedical scientists, and trainees in oncology and pharmacology who are interested in learning how to improve their research by using early phase trials. Brings a comprehensive review and recommendations for new clinical trial designs for modern cancer therapeutics Provides the reader with a better understanding on how to design and implement early phase oncology trials Presents a better and updated understanding of the process of developing new treatments for cancer, the exciting scientific advances and how they are informing drug development

Oncology Clinical Trials

Oncology Clinical Trials Book
Author : Susan Halabi, PhD,Wm. Kevin Kelly, DO
Publisher : Demos Medical Publishing
Release : 2009-12-22
ISBN : 9781935281764
Language : En, Es, Fr & De

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Book Description :

Clinical trials are the engine of progress in the development of new drugs and devices for the detection, monitoring, prevention and treatment of cancer. A well conceived, carefully designed and efficiently conducted clinical trial can produce results that change clinical practice overnight, deliver new oncology drugs and diagnostics to the marketplace, and expand the horizon of contemporary thinking about cancer biology. A poorly done trial does little to advance the field or guide clinical practice, consumes precious clinical and financial resources and challenges the validity of the ethical contract between investigators and the volunteers who willingly give their time and effort to benefit future patients. With chapters written by oncologists, researchers, biostatisticians, clinical research administrators, and industry and FDA representatives, Oncology Clinical Trials, provides a comprehensive guide for both early-career and senior oncology investigators into the successful design, conduct and analysis of an oncology clinical trial. Oncology Clinical Trials covers how to formulate a study question, selecting a study population, study design of Phase I, II, and III trials, toxicity monitoring, data analysis and reporting, use of genomics, cost-effectiveness analysis, systemic review and meta-analysis, and many other issues. Many examples of real-life flaws in clinical trials that have been reported in the literature are included throughout. The book discusses clinical trials from start to finish focusing on real-life examples in the development, design and analysis of clinical trials. Oncology Clinical Trials features: A systematic guide to all aspects of the design, conduct, analysis, and reporting of clinical trials in oncology Contributions from oncologists, researchers, biostatisticians, clinical research administrators, and industry and FDA representatives Hot topics in oncology trials including multi-arm trials, meta-analysis and adaptive design, use of genomics, and cost-effectiveness analysis Real-life examples from reported clinical trials included throughout

Statistical Approaches in Oncology Clinical Development

Statistical Approaches in Oncology Clinical Development Book
Author : Satrajit Roychoudhury,Soumi Lahiri
Publisher : CRC Press
Release : 2018-12-07
ISBN : 1351650475
Language : En, Es, Fr & De

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Book Description :

Statistical Approaches in Oncology Clinical Development : Current Paradigm and Methodological Advancement presents an overview of statistical considerations in oncology clinical trials, both early and late phase of development. It illustrates how novel statistical methods can enrich the design and analysis of modern oncology trials. The authors include many relevant real life examples from the pharmaceutical industry and academia based on their first-hand experience. Along with relevant references, the book highlights current regulatory views. The book covers all aspects of cancer clinical trial starting from early phase development. The early part of the book covers novel phase I dose escalation design, exposure response analysis, and innovative phase II design. This includes early development strategy for cancer immunotherapy trials. The contributors also emphasized the role of biomarker and modern era of precision medicine. The second part focuses on the late stage development. This includes the application of adaptive design, safety analysis, and quality of life (QoL) data analysis. The final part discusses current regulatory perspective and challenges. Features: Covers a wide spectrum of topics related to real-life statistical challenges in oncology clinical trials. Provides a comprehensive overview of novel statistical methods to improve trial design and statistical analysis. Detailed case studies illustrate the real life applications. Satrajit Roychoudhury is a Senior Director and a member of the Statistical Research and Innovation group in Pfizer Inc. Prior to joining; he was a member of Statistical Methodology and consulting group in Novartis. He has 11 years of extensive experience in working with different phases of clinical trial. His area of research includes early phase oncology trials, survival analysis, model informed drug development, and use of Bayesian methods in clinical trials. He is industry co-chair for the ASA Biopharmaceutical Section Regulatory-Industry Workshop and has provided statistical training in major conferences including the Joint Statistical Meetings, ASA Biopharmaceutical Section Regulatory-Industry Workshop, and ICSA Applied Statistics Symposium. Soumi Lahiri has 12 years of extensive experience in working different therapeutic areas. She is the former Director of Biostatistics in Clinical Oncology, GlaxoSmithKline. She has also worked in the oncology division of Novartis Pharmaceutical Company for two years. She is an active member of the ASA Biopharmaceutical section and former chair of the membership committee.

Designs for Clinical Trials

Designs for Clinical Trials Book
Author : David Harrington
Publisher : Springer Science & Business Media
Release : 2011-10-09
ISBN : 9781461401407
Language : En, Es, Fr & De

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Book Description :

This book will examine current issues and controversies in the design of clinical trials, including topics in adaptive and sequential designs, the design of correlative genomic studies, the design of studies in which missing data is anticipated. Each chapter will be written by an expert conducting research in the topic of that chapter. As a collection, the chapters would be intended to serve as a guidance for statisticians designing trials.

Phase I Oncology Drug Development

Phase I Oncology Drug Development Book
Author : Timothy A. Yap,Jordi Rodon,David S. Hong
Publisher : Springer Nature
Release : 2020-09-16
ISBN : 3030476820
Language : En, Es, Fr & De

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Book Description :

This book provides a detailed review of how oncology drug development has changed over the past decade, and serves as a comprehensive guide for the practicalities in setting up phase I trials. The book covers strategies to accelerate the development of novel antitumor compounds from the laboratory to clinical trials and beyond through the use of innovative mechanism-of-action pharmacodynamic biomarkers and pharmacokinetic studies. The reader will learn about all aspects of modern phase I trial designs, including the incorporation of precision medicine strategies, and approaches for rational patient allocation to novel anticancer therapies. Circulating biomarkers to assess mechanisms of response and resistance are changing the way we are assessing patient selection and are also covered in this book. The development of the different classes of antitumor agents are discussed, including chemotherapy, molecularly targeted agents, immunotherapies and also radiotherapy. The authors also discuss the lessons that the oncology field has learnt from the development of hematology-oncology drugs and how such strategies can be carried over into therapies for solid tumors. There is a dedicated chapter that covers the specialized statistical approaches necessary for phase I trial designs, including novel Bayesian strategies for dose escalation. This volume is designed to help clinicians better understand phase I clinical trials, but would also be of use to translational researchers (MDs and PhDs), and drug developers from academia and industry interested in cancer drug development. It could also be of use to phase I trial study coordinators, oncology nurses and advanced practice providers. Other health professionals interested in the treatment of cancer will also find this book of great value.

Dose Finding Designs for Early Phase Cancer Clinical Trials

Dose Finding Designs for Early Phase Cancer Clinical Trials Book
Author : Takashi Daimon,Akihiro Hirakawa,Shigeyuki Matsui
Publisher : Springer
Release : 2019-05-21
ISBN : 4431555854
Language : En, Es, Fr & De

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Book Description :

This book provides a comprehensive introduction to statistical methods for designing early phase dose-finding clinical trials. It will serve as a textbook or handbook for graduate students and practitioners in biostatistics and clinical investigators who are involved in designing, conducting, monitoring, and analyzing dose-finding trials. The book will also provide an overview of advanced topics and discussions in this field for the benefit of researchers in biostatistics and statistical science. Beginning with backgrounds and fundamental notions on dose finding in early phase clinical trials, the book then provides traditional and recent dose-finding designs of phase I trials for, e.g., cytotoxic agents in oncology, to evaluate toxicity outcome. Included are rule-based and model-based designs, such as 3 + 3 designs, accelerated titration designs, toxicity probability interval designs, continual reassessment method and related designs, and escalation overdose control designs. This book also covers more complex and updated dose-finding designs of phase I-II and I/II trials for cytotoxic agents, and cytostatic agents, focusing on both toxicity and efficacy outcomes, such as designs with covariates and drug combinations, maximum tolerated dose-schedule finding designs, and so on.

Platform Trial Designs in Drug Development

Platform Trial Designs in Drug Development Book
Author : Zoran Antonijevic,Robert A. Beckman
Publisher : CRC Press
Release : 2018-12-07
ISBN : 1351683926
Language : En, Es, Fr & De

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Book Description :

Platform trials test multiple therapies in one indication, one therapy for multiple indications, or both. These novel clinical trial designs can dramatically increase the cost-effectiveness of drug development, leading to life-altering medicines for people suffering from serious illnesses, possibly at lower cost. Currently, the cost of drug development is unsustainable. Furthermore, there are particular problems in rare diseases and small biomarker defined subsets in oncology, where the required sample sizes for traditional clinical trial designs may not be feasible. The editors recruited the key innovators in this domain. The 20 articles discuss trial designs from perspectives as diverse as quantum computing, patient’s rights to information, and international health. The book begins with an overview of platform trials from multiple perspectives. It then describes impacts of platform trials on the pharmaceutical industry’s key stakeholders: patients, regulators, and payers. Next it provides advanced statistical methods that address multiple aspects of platform trials, before concluding with a pharmaceutical executive’s perspective on platform trials. Except for the statistical methods section, only a basic qualitative knowledge of clinical trials is needed to appreciate the important concepts and novel ideas presented.

A Practical Guide to Designing Phase II Trials in Oncology

A Practical Guide to Designing Phase II Trials in Oncology Book
Author : Sarah R. Brown,Walter M. Gregory,Christopher J. Twelves,Julia M. Brown
Publisher : John Wiley & Sons
Release : 2014-03-28
ISBN : 1118763637
Language : En, Es, Fr & De

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Book Description :

How to identify optimal phase II trial designs Providing a practical guide containing the information needed to make crucial decisions regarding phase II trial designs, A Practical Guide to Designing Phase II Trials in Oncology sets forth specific points for consideration between the statistician and clinician when designing a phase II trial, including issues such as how the treatment works, choice of outcome measure and randomization, and considering both academic and industry perspectives. A comprehensive and systematic library of available phase II trial designs is included, saving time otherwise spent considering multiple manuscripts, and real-life practical examples of using this approach to design phase II trials in cancer are given. A Practical Guide to Designing Phase II Trials in Oncology: Offers a structured and practical approach to phase II trial design Considers trial design from both an academic and industry perspective Includes a structured library of available phase II trial designs Is relevant to both clinical and statistical researchers at all levels Includes real life examples of applying this approach For those new to trial design, A Practical Guide to Designing Phase II Trials in Oncology will be a unique and practical learning tool, providing an introduction to the concepts behind informed decision making in phase II trials. For more experienced practitioners, the book will offer an overview of new, less familiar approaches to phase II trial design, providing alternative options to those which they may have previously used.

Handbook of Statistics in Clinical Oncology Third Edition

Handbook of Statistics in Clinical Oncology  Third Edition Book
Author : John Crowley,Antje Hoering
Publisher : CRC Press
Release : 2012-03-26
ISBN : 1439862001
Language : En, Es, Fr & De

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Book Description :

Many new challenges have arisen in the area of oncology clinical trials. New cancer therapies are often based on cytostatic or targeted agents, which pose new challenges in the design and analysis of all phases of trials. The literature on adaptive trial designs and early stopping has been exploding. Inclusion of high-dimensional data and imaging techniques have become common practice, and statistical methods on how to analyse such data have been refined in this area. A compilation of statistical topics relevant to these new advances in cancer research, this third edition of Handbook of Statistics in Clinical Oncology focuses on the design and analysis of oncology clinical trials and translational research. Addressing the many challenges that have arisen since the publication of its predecessor, this third edition covers the newest developments involved in the design and analysis of cancer clinical trials, incorporating updates to all four parts: Phase I trials: Updated recommendations regarding the standard 3 + 3 and continual reassessment approaches, along with new chapters on phase 0 trials and phase I trial design for targeted agents. Phase II trials: Updates to current experience in single-arm and randomized phase II trial designs. New chapters include phase II designs with multiple strata and phase II/III designs. Phase III trials: Many new chapters include interim analyses and early stopping considerations, phase III trial designs for targeted agents and for testing the ability of markers, adaptive trial designs, cure rate survival models, statistical methods of imaging, as well as a thorough review of software for the design and analysis of clinical trials. Exploratory and high-dimensional data analyses: All chapters in this part have been thoroughly updated since the last edition. New chapters address methods for analyzing SNP data and for developing a score based on gene expression data. In addition, chapters on risk calculators and forensic bioinformatics have been added. Accessible to statisticians and oncologists interested in clinical trial methodology, the book is a single-source collection of up-to-date statistical approaches to research in clinical oncology.

Phase I Cancer Clinical Trials

Phase I Cancer Clinical Trials Book
Author : Elizabeth A. Eisenhauer,Christopher Twelves,Marc Buyse
Publisher : Oxford University Press
Release : 2015-03-20
ISBN : 0199359032
Language : En, Es, Fr & De

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Book Description :

Phase I trials are a critical first step in the study of novel cancer therapeutic approaches. Their primary goals are to identify the recommended dose, schedule and pharmacologic behavior of new agents or new combinations of agents and to describe the adverse effects of treatment. In cancer therapeutics, such studies have particular challenges. Due to the nature of the effects of treatment, most such studies are conducted in patients with advanced malignancy, rather than in healthy volunteers. Further, the endpoints of these trials are usually measures adverse effects rather than molecular target or anti-tumor effects. These factors render the design, conduct, analysis and ethical aspects of phase I cancer trials unique. As the only comprehensive book on this topic, Phase I Cancer Clinical Trials is a useful resource for oncology trainees or specialists interested in understanding cancer drug development. New to this edition are chapters on Phase 0 Trials and Immunotherapeutics, and updated information on the process, pitfalls, and logistics of Phase I Trials

Bayesian Designs for Phase I II Clinical Trials

Bayesian Designs for Phase I II Clinical Trials Book
Author : Ying Yuan,Hoang Q. Nguyen,Peter F. Thall
Publisher : CRC Press
Release : 2017-12-19
ISBN : 1498709567
Language : En, Es, Fr & De

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Book Description :

Reliably optimizing a new treatment in humans is a critical first step in clinical evaluation since choosing a suboptimal dose or schedule may lead to failure in later trials. At the same time, if promising preclinical results do not translate into a real treatment advance, it is important to determine this quickly and terminate the clinical evaluation process to avoid wasting resources. Bayesian Designs for Phase I–II Clinical Trials describes how phase I–II designs can serve as a bridge or protective barrier between preclinical studies and large confirmatory clinical trials. It illustrates many of the severe drawbacks with conventional methods used for early-phase clinical trials and presents numerous Bayesian designs for human clinical trials of new experimental treatment regimes. Written by research leaders from the University of Texas MD Anderson Cancer Center, this book shows how Bayesian designs for early-phase clinical trials can explore, refine, and optimize new experimental treatments. It emphasizes the importance of basing decisions on both efficacy and toxicity.

Oncology Clinical Trials

Oncology Clinical Trials Book
Author : William Kevin Kelly, DO,Susan Halabi, PhD
Publisher : Springer Publishing Company
Release : 2018-03-28
ISBN : 0826168736
Language : En, Es, Fr & De

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Book Description :

The second edition of Oncology Clinical Trials has been thoroughly revised and updated and now contains the latest designs and methods of conducting and analyzing cancer clinical trials in the era of precision medicine with biologic agents—including trials investigating the safety and efficacy of targeted therapies, immunotherapies, and combination therapies as well as novel radiation therapy modalities. Now divided into six sections this revamped book provides the necessary background and expert guidance from the principles governing oncology clinical trials to the innovative statistical design methods permeating the field; from conducting trials in a safe and effective manner, analyzing and interpreting the data, to a forward-looking assessment and discussion of regulatory issues impacting domestic, international, and global clinical trials. Considered by many as the gold standard reference on oncology clinical trials in the field, the second edition continues to provide examples of real-life flaws and real-world examples for how to successfully design, conduct and analyze quality clinical trials and interpret them. With chapters written by oncologists, researchers, biostatisticians, clinical research administrators, and industry and FDA representatives, this volume provides a comprehensive guide in the design, conduct, monitoring, analysis, and reporting of clinical trials in oncology. NEW TO THIS EDITION: Outlines how to design clinical trials with and without biomarker testing—including genomics-based “basket” trials, and adaptive trials for all phases during treatment and quality-of-life trials Includes new chapters on immunotherapy trials, radiation therapy trials, multi-arm trials, meta-analysis and adaptive design, use of genomics, dose modifications and use of ancillary treatments in investigational studies, establishing surrogate endpoints, practical issues with correlative studies, cost-effectiveness analysis, and more Comprehensively covers all regulatory aspects in the pursuit of global oncology trials Digital access to the ebook included

Clinical Trial Design

Clinical Trial Design Book
Author : Guosheng Yin
Publisher : John Wiley & Sons
Release : 2013-06-07
ISBN : 1118183320
Language : En, Es, Fr & De

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Book Description :

A balanced treatment of the theories, methodologies, and designissues involved in clinical trials using statisticalmethods There has been enormous interest and development in Bayesianadaptive designs, especially for early phases of clinical trials.However, for phase III trials, frequentist methods still play adominant role through controlling type I and type II errors in thehypothesis testing framework. From practical perspectives, ClinicalTrial Design: Bayesian and Frequentist Adaptive Methods providescomprehensive coverage of both Bayesian and frequentist approachesto all phases of clinical trial design. Before underpinning variousadaptive methods, the book establishes an overview of thefundamentals of clinical trials as well as a comparison of Bayesianand frequentist statistics. Recognizing that clinical trial design is one of the mostimportant and useful skills in the pharmaceutical industry, thisbook provides detailed discussions on a variety of statisticaldesigns, their properties, and operating characteristics for phaseI, II, and III clinical trials as well as an introduction to phaseIV trials. Many practical issues and challenges arising in clinicaltrials are addressed. Additional topics of coverage include: Risk and benefit analysis for toxicity and efficacytrade-offs Bayesian predictive probability trial monitoring Bayesian adaptive randomization Late onset toxicity and response Dose finding in drug combination trials Targeted therapy designs The author utilizes cutting-edge clinical trial designs andstatistical methods that have been employed at the world's leadingmedical centers as well as in the pharmaceutical industry. Thesoftware used throughout the book is freely available on the book'srelated website, equipping readers with the necessary tools fordesigning clinical trials. Clinical Trial Design is an excellent book for courses on thetopic at the graduate level. The book also serves as a valuablereference for statisticians and biostatisticians in thepharmaceutical industry as well as for researchers andpractitioners who design, conduct, and monitor clinical trials intheir everyday work.

Exploring Novel Clinical Trial Designs for Gene Based Therapies

Exploring Novel Clinical Trial Designs for Gene Based Therapies Book
Author : National Academies of Sciences, Engineering, and Medicine,Health and Medicine Division,Board on Health Sciences Policy,Forum on Regenerative Medicine
Publisher : National Academies Press
Release : 2020-08-27
ISBN : 0309672988
Language : En, Es, Fr & De

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Book Description :

Recognizing the potential design complexities and ethical issues associated with clinical trials for gene therapies, the Forum on Regenerative Medicine of the National Academies of Sciences, Engineering, and Medicine held a 1-day workshop in Washington, DC, on November 13, 2019. Speakers at the workshop discussed patient recruitment and selection for gene-based clinical trials, explored how the safety of new therapies is assessed, reviewed the challenges involving dose escalation, and spoke about ethical issues such as informed consent and the role of clinicians in recommending trials as options to their patients. The workshop also included discussions of topics related to gene therapies in the context of other available and potentially curative treatments, such as bone marrow transplantation for hemoglobinopathies. This publication summarizes the presentation and discussion of the workshop.

Clinical Trials in Oncology Third Edition

Clinical Trials in Oncology  Third Edition Book
Author : Stephanie Green,Jacqueline Benedetti,Angela Smith,John Crowley
Publisher : CRC Press
Release : 2012-05-09
ISBN : 1439814481
Language : En, Es, Fr & De

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Book Description :

The third edition of the bestselling Clinical Trials in Oncology provides a concise, nontechnical, and thoroughly up-to-date review of methods and issues related to cancer clinical trials. The authors emphasize the importance of proper study design, analysis, and data management and identify the pitfalls inherent in these processes. In addition, the book has been restructured to have separate chapters and expanded discussions on general clinical trials issues, and issues specific to Phases I, II, and III. New sections cover innovations in Phase I designs, randomized Phase II designs, and overcoming the challenges of array data. Although this book focuses on cancer trials, the same issues and concepts are important in any clinical setting. As always, the authors use clear, lucid prose and a multitude of real-world examples to convey the principles of successful trials without the need for a strong statistics or mathematics background. Armed with Clinical Trials in Oncology, Third Edition, clinicians and statisticians can avoid the many hazards that can jeopardize the success of a trial.

Cancer Clinical Trials

Cancer Clinical Trials Book
Author : Stephen L. George,Xiaofei Wang,Herbert Pang
Publisher : CRC Press
Release : 2016-08-03
ISBN : 1315354330
Language : En, Es, Fr & De

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Book Description :

Cancer Clinical Trials: Current and Controversial Issues in Design and Analysis provides statisticians with an understanding of the critical challenges currently encountered in oncology trials. Well-known statisticians from academic institutions, regulatory and government agencies (such as the U.S. FDA and National Cancer Institute), and the pharmaceutical industry share their extensive experiences in cancer clinical trials and present examples taken from actual trials. The book covers topics that are often perplexing and sometimes controversial in cancer clinical trials. Most of the issues addressed are also important for clinical trials in other settings. After discussing general topics, the book focuses on aspects of early and late phase clinical trials. It also explores personalized medicine, including biomarker-based clinical trials, adaptive clinical trial designs, and dynamic treatment regimes.

Anticancer Drug Development Guide

Anticancer Drug Development Guide Book
Author : Beverly A. Teicher,Paul A. Andrews
Publisher : Springer Science & Business Media
Release : 2004-02-01
ISBN : 1592597394
Language : En, Es, Fr & De

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Book Description :

This unique volume traces the critically important pathway by which a "molecule" becomes an "anticancer agent. " The recognition following World War I that the administration of toxic chemicals such as nitrogen mustards in a controlled manner could shrink malignant tumor masses for relatively substantial periods of time gave great impetus to the search for molecules that would be lethal to specific cancer cells. Weare still actively engaged in that search today. The question is how to discover these "anticancer" molecules. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition describes the evolution to the present of preclinical screening methods. The National Cancer Institute's high-throughput, in vitro disease-specific screen with 60 or more human tumor cell lines is used to search for molecules with novel mechanisms of action or activity against specific phenotypes. The Human Tumor Colony-Forming Assay (HTCA) uses fresh tumor biopsies as sources of cells that more nearly resemble the human disease. There is no doubt that the greatest successes of traditional chemotherapy have been in the leukemias and lymphomas. Since the earliest widely used in vivo drug screening models were the murine L 1210 and P388 leukemias, the community came to assume that these murine tumor models were appropriate to the discovery of "antileukemia" agents, but that other tumor models would be needed to discover drugs active against solid tumors.

Handbook of Methods for Designing Monitoring and Analyzing Dose Finding Trials

Handbook of Methods for Designing  Monitoring  and Analyzing Dose Finding Trials Book
Author : John O'Quigley,Alexia Iasonos,Björn Bornkamp
Publisher : CRC Press
Release : 2017-04-27
ISBN : 1351648020
Language : En, Es, Fr & De

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Book Description :

Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials gives a thorough presentation of state-of-the-art methods for early phase clinical trials. The methodology of clinical trials has advanced greatly over the last 20 years and, arguably, nowhere greater than that of early phase studies. The need to accelerate drug development in a rapidly evolving context of targeted therapies, immunotherapy, combination treatments and complex group structures has provided the stimulus to these advances. Typically, we deal with very small samples, sequential methods that need to be efficient, while, at the same time adhering to ethical principles due to the involvement of human subjects. Statistical inference is difficult since the standard techniques of maximum likelihood do not usually apply as a result of model misspecification and parameter estimates lying on the boundary of the parameter space. Bayesian methods play an important part in overcoming these difficulties, but nonetheless, require special consideration in this particular context. The purpose of this handbook is to provide an expanded summary of the field as it stands and also, through discussion, provide insights into the thinking of leaders in the field as to the potential developments of the years ahead. With this goal in mind we present: An introduction to the field for graduate students and novices A basis for more established researchers from which to build A collection of material for an advanced course in early phase clinical trials A comprehensive guide to available methodology for practicing statisticians on the design and analysis of dose-finding experiments An extensive guide for the multiple comparison and modeling (MCP-Mod) dose-finding approach, adaptive two-stage designs for dose finding, as well as dose–time–response models and multiple testing in the context of confirmatory dose-finding studies. John O’Quigley is a professor of mathematics and research director at the French National Institute for Health and Medical Research based at the Faculty of Mathematics, University Pierre and Marie Curie in Paris, France. He is author of Proportional Hazards Regression and has published extensively in the field of dose finding. Alexia Iasonos is an associate attending biostatistician at the Memorial Sloan Kettering Cancer Center in New York. She has over one hundred publications in the leading statistical and clinical journals on the methodology and design of early phase clinical trials. Dr. Iasonos has wide experience in the actual implementation of model based early phase trials and has given courses in scientific meetings internationally. Björn Bornkamp is a statistical methodologist at Novartis in Basel, Switzerland, researching and implementing dose-finding designs in Phase II clinical trials. He is one of the co-developers of the MCP-Mod methodology for dose finding and main author of the DoseFinding R package. He has published numerous papers on dose finding, nonlinear models and Bayesian statistics, and in 2013 won the Royal Statistical Society award for statistical excellence in the pharmaceutical industry.

An Iterative Phase I II I Clinical Trial Design Incorporating Genomic Biomarker Information

An Iterative Phase I II I Clinical Trial Design Incorporating Genomic Biomarker Information Book
Author : Ashok Krishnamurthy
Publisher : Unknown
Release : 2009
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

The goal of a phase I cancer clinical trial is to determine the maximum tolerated dose (MTD) or the recommended phase II dose (RP2D) of a new drug that corresponds to some given acceptable rate of dose limiting toxicity. However, a common limitation to the generalizability of phase I and phase II clinical trials is high patient heterogeneity with respect to toxicity and efficacy. A poor estimate of the MTD may put patients at unprecedented risks by assigning subtherapeutic or excessively toxic doses. Ignoring patient heterogeneity with respect to efficacy may cause phase II trials to have extremely large false positive and false negative error rates within subpopulations. In either case, the large scale phase III clinical trial conducted with an inappropriate dose may put patients in the study at high risk, and doom a potential effective and safe treatment after substantial investment in its development. It is believed that most cancer clinical trials involve a heterogeneous group of patients at the molecular level. This heterogeneity is one of the reasons that not all patients with cancer respond to a given drug. In view of this patient heterogeneity, it is clear that a "one size fits all" approach may not be suitable in the drug development process. Therefore, it is important to be able to predict which patients are most likely to benefit from a new drug. This would not only save patients from unnecessary risk of toxicity but might facilitate their receiving beneficial treatment, and it would shorten the time required for drug development and lower associated costs. The goals of this research are two fold: (1) to investigate statistical issues involved in applying a genomic biomarker classification method to account for patient heterogeneity with respect to toxicity and efficacy response in early phase clinical trials, allowing for the possibility of differing treatment efficacy among subpopulations, and (2) developing a new design approach that incorporates high-dimensional genomic information into phase I/II clinical trials. We propose to achieve this goal by using a novel compound iterative phase I/II/I clinical trial design which may be conceptualized into three stages. The first stage consists of obtaining an overall estimate of the MTD based on an initial phase I trial under the assumption of no patient heterogeneity. A phase II study is then conducted using the preliminary estimate of the MTD to estimate efficacy. The second stage focuses on the application of the predictive classifiers in early phases of clinical trials. Supervised learning algorithms (i.e., support vector machines (SVM)) are effective classification tools in high-dimensional microarray classification problems such as the development of genomic biomarkers from microarray data. We implemented the SVM binary classification algorithm using the approach of Xu (2008) for the development of predictive classifiers based on phase II trial efficacy data by comparing the gene-expression profiles of responders versus non-responders. Identification of patient subpopulations that might be expected to have distinct toxicity/efficacy profiles may thus be based on genomic biomarkers. The third stage of our proposed design incorporates the predictive classifier described above to estimate and refine the MTD through two key steps: (1) obtain an estimated MTD for each biomarker group by combining toxicity data from the first two stages and applying an estimation algorithm and (2) refine the MTD estimate by conducting a secondary phase I trial for each biomarker group. The secondary phase I trials account for patient heterogeneity by basing dose finding on toxicity while also accounting for each patient's genomic biomarker status. This provides a mechanism for incorporating genomic information that permits estimation of separate MTDs for the two subpopulations identified by the biomarker. We compared various MTD estimation methods, and based on the results of simulation studies recommended the use of the constrained logistic regression model to estimate biomarker group-specific MTDs prior to the secondary phase I studies. We investigated the impact of two adaptive design strategies in the secondary phase I trials across a range of dose-toxicity and dose-efficacy profiles. Our results showed that by applying predictive classifiers to determine a MTD estimate for each subpopulation we can obtain an acceptably large value of probability of efficacy (i.e., improved response rates) while also controlling the probability of toxicity (i.e., increased safety) for each subpopulation. We concluded that the MTD estimates obtained from our proposed design are more accurate than would be expected from a single phase I trial. The results of this research provide important guidelines with respect to (1) incorporating genomic biomarker information from microarray data into early phase clinical trials to identify subpopulations and (2) use of predictive classifiers to obtain refined and improved estimates of MTDs for subpopulations.

Biomarkers of the Tumor Microenvironment

Biomarkers of the Tumor Microenvironment Book
Author : Lars A. Akslen,Randolph S. Watnick
Publisher : Springer
Release : 2017-08-02
ISBN : 331939147X
Language : En, Es, Fr & De

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Book Description :

This book reviews different aspects of the cancer microenvironment, and its regulation and importance for tumor progression. Practical applications, in terms of how biomarkers are increasingly included in therapy protocols, will also be discussed. Biomarkers of the Tumor Microenvironment: Basic Studies and Practical Applications is aimed at research pathologists in the cancer field, and also cancer researchers from other backgrounds, especially those using morphology techniques and models focusing on cross-talk between different cell types in tumors.