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| dose escalation study design: Phase I Cancer Clinical Trials Elizabeth A. Eisenhauer, Chris Twelves, Marc E. Buyse, 2014-06 Phase I trials are a critical first step in the study of novel cancer therapeutic approaches. As this title is the only comprehensive book on this topic, it 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. |
| dose escalation study design: Clinical Trials in Oncology, Third Edition Stephanie Green, Jacqueline Benedetti, Angela Smith, John Crowley, 2012-05-09 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. |
| dose escalation study design: Bayesian Designs for Phase I-II Clinical Trials Ying Yuan, Hoang Q. Nguyen, Peter F. Thall, 2017-12-19 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. |
| dose escalation study design: The Prevention and Treatment of Missing Data in Clinical Trials National Research Council, Division of Behavioral and Social Sciences and Education, Committee on National Statistics, Panel on Handling Missing Data in Clinical Trials, 2010-12-21 Randomized clinical trials are the primary tool for evaluating new medical interventions. Randomization provides for a fair comparison between treatment and control groups, balancing out, on average, distributions of known and unknown factors among the participants. Unfortunately, these studies often lack a substantial percentage of data. This missing data reduces the benefit provided by the randomization and introduces potential biases in the comparison of the treatment groups. Missing data can arise for a variety of reasons, including the inability or unwillingness of participants to meet appointments for evaluation. And in some studies, some or all of data collection ceases when participants discontinue study treatment. Existing guidelines for the design and conduct of clinical trials, and the analysis of the resulting data, provide only limited advice on how to handle missing data. Thus, approaches to the analysis of data with an appreciable amount of missing values tend to be ad hoc and variable. The Prevention and Treatment of Missing Data in Clinical Trials concludes that a more principled approach to design and analysis in the presence of missing data is both needed and possible. Such an approach needs to focus on two critical elements: (1) careful design and conduct to limit the amount and impact of missing data and (2) analysis that makes full use of information on all randomized participants and is based on careful attention to the assumptions about the nature of the missing data underlying estimates of treatment effects. In addition to the highest priority recommendations, the book offers more detailed recommendations on the conduct of clinical trials and techniques for analysis of trial data. |
| dose escalation study design: Principles and Practice of Clinical Trials Steven Piantadosi, Curtis L. Meinert, 2022-07-19 This is a comprehensive major reference work for our SpringerReference program covering clinical trials. Although the core of the Work will focus on the design, analysis, and interpretation of scientific data from clinical trials, a broad spectrum of clinical trial application areas will be covered in detail. This is an important time to develop such a Work, as drug safety and efficacy emphasizes the Clinical Trials process. Because of an immense and growing international disease burden, pharmaceutical and biotechnology companies continue to develop new drugs. Clinical trials have also become extremely globalized in the past 15 years, with over 225,000 international trials ongoing at this point in time. Principles in Practice of Clinical Trials is truly an interdisciplinary that will be divided into the following areas: 1) Clinical Trials Basic Perspectives 2) Regulation and Oversight 3) Basic Trial Designs 4) Advanced Trial Designs 5) Analysis 6) Trial Publication 7) Topics Related Specific Populations and Legal Aspects of Clinical Trials The Work is designed to be comprised of 175 chapters and approximately 2500 pages. The Work will be oriented like many of our SpringerReference Handbooks, presenting detailed and comprehensive expository chapters on broad subjects. The Editors are major figures in the field of clinical trials, and both have written textbooks on the topic. There will also be a slate of 7-8 renowned associate editors that will edit individual sections of the Reference. |
| dose escalation study design: Dose Finding by the Continual Reassessment Method Ying Kuen Cheung, 2011-03-29 As clinicians begin to realize the important role of dose-finding in the drug development process, there is an increasing openness to novel methods proposed in the past two decades. In particular, the Continual Reassessment Method (CRM) and its variations have drawn much attention in the medical community, though it has yet to become a commonplace tool. To overcome the status quo in phase I clinical trials, statisticians must be able to design trials using the CRM in a timely and reproducible manner. A self-contained theoretical framework of the CRM for researchers and graduate students who set out to learn and do research in the CRM and dose-finding methods in general, Dose Finding by the Continual Reassessment Method features: Real clinical trial examples that illustrate the methods and techniques throughout the book Detailed calibration techniques that enable biostatisticians to design a CRM in timely manner Limitations of the CRM are outlined to aid in correct use of method This book supplies practical, efficient dose-finding methods based on cutting edge statistical research. More than just a cookbook, it provides full, unified coverage of the CRM in addition to step-by-step guidelines to automation and parameterization of the methods used on a regular basis. A detailed exposition of the calibration of the CRM for applied statisticians working with dose-finding in phase I trials, the book focuses on the R package ‘dfcrm’ for the CRM and its major variants. The author recognizes clinicians’ skepticism of model-based designs, and addresses their concerns that the time, professional, and computational resources necessary for accurate model-based designs can be major bottlenecks to the widespread use of appropriate dose-finding methods in phase I practice. The theoretically- and empirically-based methods in Dose Finding by the Continual Reassessment Method will lessen the statistician’s burden and encourage the continuing development and implementation of model-based dose-finding methods. |
| dose escalation study design: Handbook of Statistics in Clinical Oncology John Crowley, Antje Hoering, Donna Ankerst, 2005-12-01 A compendium of cutting-edge statistical approaches to solving problems in clinical oncology, Handbook of Statistics in Clinical Oncology, Second Edition focuses on clinical trials in phases I, II, and III, proteomic and genomic studies, complementary outcomes and exploratory methods. Cancer Forum called the first edition a |
| dose escalation study design: Drug Discovery and Evaluation: Methods in Clinical Pharmacology H.Gerhard Vogel, Jochen Maas, Alexander Gebauer, 2010-12-15 Drug Discovery and Evaluation has become a more and more difficult, expensive and time-consuming process. The effect of a new compound has to be detected by in vitro and in vivo methods of pharmacology. The activity spectrum and the potency compared to existing drugs have to be determined. As these processes can be divided up stepwise we have designed a book series Drug Discovery and Evaluation in the form of a recommendation document. The methods to detect drug targets are described in the first volume of this series Pharmacological Assays comprising classical methods as well as new technologies. Before going to man, the most suitable compound has to be selected by pharmacokinetic studies and experiments in toxicology. These preclinical methods are described in the second volume „Safety and Pharmacokinetic Assays. Only then are first studies in human beings allowed. Special rules are established for Phase I studies. Clinical pharmacokinetics are performed in parallel with human studies on tolerability and therapeutic effects. Special studies according to various populations and different therapeutic indications are necessary. These items are covered in the third volume: „Methods in Clinical Pharmacology. |
| dose escalation study design: Statistical Methods for Dose-Finding Experiments Sylvie Chevret, 2006-05-26 Dose-finding experiments define the safe dosage of a drug in development, in terms of the quantity given to a patient. Statistical methods play a crucial role in identifying optimal dosage. Used appropriately, these methods provide reliable results and reduce trial duration and costs. In practice, however, dose-finding is often done poorly, with widely used conventional methods frequently being unreliable, leading to inaccurate results. However, there have been many advances in recent years, with new statistical techniques being developed and it is important that these new techniques are utilized correctly. Statistical Methods for Dose-Finding Experiments reviews the main statistical approaches for dose-finding in phase I/II clinical trials and presents practical guidance on their correct use. Includes an introductory section, summarizing the essential concepts in dose-finding. Contains a section on algorithm-based approaches, such as the traditional 3+3 design, and a section on model-based approaches, such as the continual reassessment method. Explains fundamental issues, such as how to stop trials early and how to cope with delayed or ordinal outcomes. Discusses in detail the main websites and software used to implement the methods. Features numerous worked examples making use of real data. Statistical Methods for Dose-Finding Experiments is an important collaboration from the leading experts in the area. Primarily aimed at statisticians and clinicians working in clinical trials and medical research, there is also much to benefit graduate students of biostatistics. |
| dose escalation study design: Practical Considerations for Adaptive Trial Design and Implementation Weili He, José Pinheiro, Olga M. Kuznetsova, 2014-10-15 This edited volume is a definitive text on adaptive clinical trial designs from creation and customization to utilization. As this book covers the full spectrum of topics involved in the adaptive designs arena, it will serve as a valuable reference for researchers working in industry, government and academia. The target audience is anyone involved in the planning and execution of clinical trials, in particular, statisticians, clinicians, pharmacometricians, clinical operation specialists, drug supply managers, and infrastructure providers. In spite of the increased efficiency of adaptive trials in saving costs and time, ultimately getting drugs to patients sooner, their adoption in clinical development is still relatively low. One of the chief reasons is the higher complexity of adaptive design trials as compared to traditional trials. Barriers to the use of clinical trials with adaptive features include the concerns about the integrity of study design and conduct, the risk of regulatory non-acceptance, the need for an advanced infrastructure for complex randomization and clinical supply scenarios, change management for process and behavior modifications, extensive resource requirements for the planning and design of adaptive trials and the potential to relegate key decision makings to outside entities. There have been limited publications that address these practical considerations and recommend best practices and solutions. This book fills this publication gap, providing guidance on practical considerations for adaptive trial design and implementation. The book comprises three parts: Part I focuses on practical considerations from a design perspective, whereas Part II delineates practical considerations related to the implementation of adaptive trials. Putting it all together, Part III presents four illustrative case studies ranging from description and discussion of specific adaptive trial design considerations to the logistic and regulatory issues faced in trial implementation. Bringing together the expertise of leading key opinion leaders from pharmaceutical industry, academia, and regulatory agencies, this book provides a balanced and comprehensive coverage of practical considerations for adaptive trial design and implementation. |
| dose escalation study design: Clinical Pharmacy Education, Practice and Research Dixon Thomas, 2018-11-23 Clinical Pharmacy Education, Practice and Research offers readers a solid foundation in clinical pharmacy and related sciences through contributions by 83 leading experts in the field from 25 countries. This book stresses educational approaches that empower pharmacists with patient care and research competencies. The learning objectives and writing style of the book focus on clarifying the concepts comprehensively for a pharmacist, from regular patient counseling to pharmacogenomics practice. It covers all interesting topics a pharmacist should know. This book serves as a basis to standardize and coordinate learning to practice, explaining basics and using self-learning strategies through online resources or other advanced texts. With an educational approach, it guides pharmacy students and pharmacists to learn quickly and apply. Clinical Pharmacy Education, Practice and Research provides an essential foundation for pharmacy students and pharmacists globally. - Covers the core information needed for pharmacy practice courses - Includes multiple case studies and practical situations with 70% focused on practical clinical pharmacology knowledge - Designed for educational settings, but also useful as a refresher for advanced students and researchers |
| dose escalation study design: Adenocarcinoma of the Prostate Andrew W. Bruce, John Trachtenberg, 2012-12-06 Carcinoma of the prostate increasingly dominates the attention of urologists for both scientific and clinical reasons. The search for an explanation and the prediction of the variable behaviour of the malignant prostatic cell continues unabated. The search for more precise tumour staging and more effective treatment is equally vigorous. Editors Andrew Bruce and John Trachtenberg have assembled acknowledged leaders in prostate cancer to present those areas of direct interest to the clinician. There are a number of other topics that might have been considered but most of these, such as experimental tumour models or biochemical factors affecting cell growth, still lack immediate application for the clinician. Carcinoma of the prostate continues to have its highest incidence in the western world, and the difference in comparison with the incidence in the Far East appears to be real and not masked by diagnostic or other factors. A number of other epidemiological aspects need careful analysis: Is the incidence increasing? Is the survival improving? Is the prognosis worse in the younger patient? Epidemiological data are easily misused and misinterpreted so that a precise analysis of the known facts makes an important opening chapter to this book. |
| dose escalation study design: Modern Approaches to Clinical Trials Using SAS Sandeep Menon, Richard C. Zink, 2015-12-09 Get the tools you need to use SAS® in clinical trial design! Unique and multifaceted, Modern Approaches to Clinical Trials Using SAS: Classical, Adaptive, and Bayesian Methods, edited by Sandeep M. Menon and Richard C. Zink, thoroughly covers several domains of modern clinical trial design: classical, group sequential, adaptive, and Bayesian methods that are applicable to and widely used in various phases of pharmaceutical development. Written for biostatisticians, pharmacometricians, clinical developers, and statistical programmers involved in the design, analysis, and interpretation of clinical trials, as well as students in graduate and postgraduate programs in statistics or biostatistics, the book touches on a wide variety of topics, including dose-response and dose-escalation designs; sequential methods to stop trials early for overwhelming efficacy, safety, or futility; Bayesian designs that incorporate historical data; adaptive sample size re-estimation; adaptive randomization to allocate subjects to more effective treatments; and population enrichment designs. Methods are illustrated using clinical trials from diverse therapeutic areas, including dermatology, endocrinology, infectious disease, neurology, oncology, and rheumatology. Individual chapters are authored by renowned contributors, experts, and key opinion leaders from the pharmaceutical/medical device industry or academia. Numerous real-world examples and sample SAS code enable users to readily apply novel clinical trial design and analysis methodologies in practice. |
| dose escalation study design: Planning Clinical Research Robert A. Parker, Nancy G. Berman, 2016-10-12 Planning clinical research requires many decisions. The authors of this book explain key decisions with examples showing what works and what does not. |
| dose escalation study design: Adaptive Design Methods in Clinical Trials Shein-Chung Chow, Mark Chang, 2011-12-01 With new statistical and scientific issues arising in adaptive clinical trial design, including the U.S. FDA's recent draft guidance, a new edition of one of the first books on the topic is needed. Adaptive Design Methods in Clinical Trials, Second Edition reflects recent developments and regulatory positions on the use of adaptive designs in clini |
| dose escalation study design: Small Clinical Trials Institute of Medicine, Board on Health Sciences Policy, Committee on Strategies for Small-Number-Participant Clinical Research Trials, 2001-01-01 Clinical trials are used to elucidate the most appropriate preventive, diagnostic, or treatment options for individuals with a given medical condition. Perhaps the most essential feature of a clinical trial is that it aims to use results based on a limited sample of research participants to see if the intervention is safe and effective or if it is comparable to a comparison treatment. Sample size is a crucial component of any clinical trial. A trial with a small number of research participants is more prone to variability and carries a considerable risk of failing to demonstrate the effectiveness of a given intervention when one really is present. This may occur in phase I (safety and pharmacologic profiles), II (pilot efficacy evaluation), and III (extensive assessment of safety and efficacy) trials. Although phase I and II studies may have smaller sample sizes, they usually have adequate statistical power, which is the committee's definition of a large trial. Sometimes a trial with eight participants may have adequate statistical power, statistical power being the probability of rejecting the null hypothesis when the hypothesis is false. Small Clinical Trials assesses the current methodologies and the appropriate situations for the conduct of clinical trials with small sample sizes. This report assesses the published literature on various strategies such as (1) meta-analysis to combine disparate information from several studies including Bayesian techniques as in the confidence profile method and (2) other alternatives such as assessing therapeutic results in a single treated population (e.g., astronauts) by sequentially measuring whether the intervention is falling above or below a preestablished probability outcome range and meeting predesigned specifications as opposed to incremental improvement. |
| dose escalation study design: Dose Finding in Drug Development Naitee Ting, 2006-12-29 If you have ever wondered when visiting the pharmacy how the dosage of your prescription is determined this book will answer your questions. Dosing information on drug labels is based on discussion between the pharmaceutical manufacturer and the drug regulatory agency, and the label is a summary of results obtained from many scientific experiments. The book introduces the drug development process, the design and the analysis of clinical trials. Many of the discussions are based on applications of statistical methods in the design and analysis of dose response studies. Important procedural steps from a pharmaceutical industry perspective are also examined. |
| dose escalation study design: Sample Size Calculations in Clinical Research Shein-Chung Chow, Jun Shao, Hansheng Wang, Yuliya Lokhnygina, 2017-08-15 Praise for the Second Edition: ... this is a useful, comprehensive compendium of almost every possible sample size formula. The strong organization and carefully defined formulae will aid any researcher designing a study. -Biometrics This impressive book contains formulae for computing sample size in a wide range of settings. One-sample studies and two-sample comparisons for quantitative, binary, and time-to-event outcomes are covered comprehensively, with separate sample size formulae for testing equality, non-inferiority, and equivalence. Many less familiar topics are also covered ... – Journal of the Royal Statistical Society Sample Size Calculations in Clinical Research, Third Edition presents statistical procedures for performing sample size calculations during various phases of clinical research and development. A comprehensive and unified presentation of statistical concepts and practical applications, this book includes a well-balanced summary of current and emerging clinical issues, regulatory requirements, and recently developed statistical methodologies for sample size calculation. Features: Compares the relative merits and disadvantages of statistical methods for sample size calculations Explains how the formulae and procedures for sample size calculations can be used in a variety of clinical research and development stages Presents real-world examples from several therapeutic areas, including cardiovascular medicine, the central nervous system, anti-infective medicine, oncology, and women’s health Provides sample size calculations for dose response studies, microarray studies, and Bayesian approaches This new edition is updated throughout, includes many new sections, and five new chapters on emerging topics: two stage seamless adaptive designs, cluster randomized trial design, zero-inflated Poisson distribution, clinical trials with extremely low incidence rates, and clinical trial simulation. |
| dose escalation study design: Randomization in Clinical Trials William F. Rosenberger, John M. Lachin, 2015-11-23 Praise for the First Edition “All medical statisticians involved in clinical trials should read this book...” - Controlled Clinical Trials Featuring a unique combination of the applied aspects of randomization in clinical trials with a nonparametric approach to inference, Randomization in Clinical Trials: Theory and Practice, Second Edition is the go-to guide for biostatisticians and pharmaceutical industry statisticians. Randomization in Clinical Trials: Theory and Practice, Second Edition features: Discussions on current philosophies, controversies, and new developments in the increasingly important role of randomization techniques in clinical trials A new chapter on covariate-adaptive randomization, including minimization techniques and inference New developments in restricted randomization and an increased focus on computation of randomization tests as opposed to the asymptotic theory of randomization tests Plenty of problem sets, theoretical exercises, and short computer simulations using SAS® to facilitate classroom teaching, simplify the mathematics, and ease readers’ understanding Randomization in Clinical Trials: Theory and Practice, Second Edition is an excellent reference for researchers as well as applied statisticians and biostatisticians. The Second Edition is also an ideal textbook for upper-undergraduate and graduate-level courses in biostatistics and applied statistics. William F. Rosenberger, PhD, is University Professor and Chairman of the Department of Statistics at George Mason University. He is a Fellow of the American Statistical Association and the Institute of Mathematical Statistics, and author of over 80 refereed journal articles, as well as The Theory of Response-Adaptive Randomization in Clinical Trials, also published by Wiley. John M. Lachin, ScD, is Research Professor in the Department of Epidemiology and Biostatistics as well as in the Department of Statistics at The George Washington University. A Fellow of the American Statistical Association and the Society for Clinical Trials, Dr. Lachin is actively involved in coordinating center activities for clinical trials of diabetes. He is the author of Biostatistical Methods: The Assessment of Relative Risks, Second Edition, also published by Wiley. |
| dose escalation study design: Dying Well Ira Byock, 1998-03-01 From Ira Byock, prominent palliative care physician and expert in end of life decisions, a lesson in Dying Well. Nobody should have to die in pain. Nobody should have to die alone. This is Ira Byock's dream, and he is dedicating his life to making it come true. Dying Well brings us to the homes and bedsides of families with whom Dr. Byock has worked, telling stories of love and reconciliation in the face of tragedy, pain, medical drama, and conflict. Through the true stories of patients, he shows us that a lot of important emotional work can be accomplished in the final months, weeks, and even days of life. It is a companion for families, showing them how to deal with doctors, how to talk to loved ones—and how to make the end of life as meaningful and enriching as the beginning. Ira Byock is also the author of The Best Care Possible: A Physician's Quest to Transform Care Through the End of Life. |
| dose escalation study design: Bayesian Adaptive Methods for Clinical Trials Scott M. Berry, Bradley P. Carlin, J. Jack Lee, Peter Muller, 2010-07-19 Already popular in the analysis of medical device trials, adaptive Bayesian designs are increasingly being used in drug development for a wide variety of diseases and conditions, from Alzheimer's disease and multiple sclerosis to obesity, diabetes, hepatitis C, and HIV. Written by leading pioneers of Bayesian clinical trial designs, Bayesian Adapti |
| dose escalation study design: Statistical Methods in Drug Combination Studies Wei Zhao, Harry Yang, 2014-12-19 The growing interest in using combination drugs to treat various complex diseases has spawned the development of many novel statistical methodologies. The theoretical development, coupled with advances in statistical computing, makes it possible to apply these emerging statistical methods in in vitro and in vivo drug combination assessments. Howeve |
| dose escalation study design: The Drug Development Paradigm in Oncology National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Health Care Services, National Cancer Policy Forum, 2018-02-12 Advances in cancer research have led to an improved understanding of the molecular mechanisms underpinning the development of cancer and how the immune system responds to cancer. This influx of research has led to an increasing number and variety of therapies in the drug development pipeline, including targeted therapies and associated biomarker tests that can select which patients are most likely to respond, and immunotherapies that harness the body's immune system to destroy cancer cells. Compared with standard chemotherapies, these new cancer therapies may demonstrate evidence of benefit and clearer distinctions between efficacy and toxicity at an earlier stage of development. However, there is a concern that the traditional processes for cancer drug development, evaluation, and regulatory approval could impede or delay the use of these promising cancer treatments in clinical practice. This has led to a number of effortsâ€by patient advocates, the pharmaceutical industry, and the Food and Drug Administration (FDA)â€to accelerate the review of promising new cancer therapies, especially for cancers that currently lack effective treatments. However, generating the necessary data to confirm safety and efficacy during expedited drug development programs can present a unique set of challenges and opportunities. To explore this new landscape in cancer drug development, the National Academies of Sciences, Engineering, and Medicine developed a workshop held in December 2016. This workshop convened cancer researchers, patient advocates, and representatives from industry, academia, and government to discuss challenges with traditional approaches to drug development, opportunities to improve the efficiency of drug development, and strategies to enhance the information available about a cancer therapy throughout its life cycle in order to improve its use in clinical practice. This publication summarizes the presentations and discussions from the workshop. |
| dose escalation study design: Exploring Novel Clinical Trial Designs for Gene-Based Therapies National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Health Sciences Policy, Forum on Regenerative Medicine, 2020-08-27 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. |
| dose escalation study design: Analysis of Clinical Trials Using SAS Alex Dmitrienko, Gary G. Koch, 2017-07-17 Analysis of Clinical Trials Using SAS®: A Practical Guide, Second Edition bridges the gap between modern statistical methodology and real-world clinical trial applications. Tutorial material and step-by-step instructions illustrated with examples from actual trials serve to define relevant statistical approaches, describe their clinical trial applications, and implement the approaches rapidly and efficiently using the power of SAS. Topics reflect the International Conference on Harmonization (ICH) guidelines for the pharmaceutical industry and address important statistical problems encountered in clinical trials. Commonly used methods are covered, including dose-escalation and dose-finding methods that are applied in Phase I and Phase II clinical trials, as well as important trial designs and analysis strategies that are employed in Phase II and Phase III clinical trials, such as multiplicity adjustment, data monitoring, and methods for handling incomplete data. This book also features recommendations from clinical trial experts and a discussion of relevant regulatory guidelines. This new edition includes more examples and case studies, new approaches for addressing statistical problems, and the following new technological updates: SAS procedures used in group sequential trials (PROC SEQDESIGN and PROC SEQTEST) SAS procedures used in repeated measures analysis (PROC GLIMMIX and PROC GEE) macros for implementing a broad range of randomization-based methods in clinical trials, performing complex multiplicity adjustments, and investigating the design and analysis of early phase trials (Phase I dose-escalation trials and Phase II dose-finding trials) Clinical statisticians, research scientists, and graduate students in biostatistics will greatly benefit from the decades of clinical research experience and the ready-to-use SAS macros compiled in this book. |
| dose escalation study design: Principles of Safety Pharmacology Michael K. Pugsley, Michael J Curtis, 2015-06-19 This book illustrates, in a comprehensive manner, the most current areas of importance to Safety Pharmacology, a burgeoning unique pharmacological discipline with important ties to academia, industry and regulatory authorities. It provides readers with a definitive collection of topics containing essential information on the latest industry guidelines and overviews current and breakthrough topics in both functional and molecular pharmacology. An additional novelty of the book is that it constitutes academic, pharmaceutical and biotechnology perspectives for Safety Pharmacology issues. Each chapter is written by an expert in the area and includes not only a fundamental background regarding the topic but also detailed descriptions of currently accepted, validated models and methods as well as innovative methodologies used in drug discovery. |
| dose escalation study design: Toxicokinetics , 1995 |
| dose escalation study design: Re-Irradiation: New Frontiers Carsten Nieder, Johannes Langendijk, 2016-10-25 This book, now in its second edition, provides a comprehensive overview of current re-irradiation strategies, with detailed discussion of re-irradiation methods, technical aspects, the role of combined therapy with anticancer drugs and hyperthermia, and normal tissue tolerance. In addition, disease specific chapters document recent clinical results and future research directions. All chapters from the first edition have been revised and updated to take account of the latest developments and research findings, including those from prospective studies. Due attention is paid to the exciting developments in the fields of proton irradiation and frameless image-guided ablative radiotherapy. The book documents fully how refined combined modality approaches and significant technical advances in radiation treatment planning and delivery have facilitated the re-irradiation of previously exposed volumes, allowing both palliative and curative approaches to be pursued at various disease sites. Professionals involved in radiation treatment planning and multimodal oncology treatment will find it to be an invaluable aid in understanding the benefits and limitations of re-irradiation and in designing prospective trials. |
| dose escalation study design: Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, 2020-04-24 Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events. |
| dose escalation study design: Reviewing Clinical Trials Chinese University of Hong Kong, Chinese University of Hong Kong. Clinical Trials Centre, Washington, DC. Association for the Accreditation of Human research Protection Programs, Inc, 2010 The idea for this manual came from Pfizer in the US, which provided the Clinical Trials Centre at The University of Hong Kong, Hong Kong SAR, PR China with a nonbinding grant for its development. The general project layout protocol was accepted by Pfizer in July 2009. Pfizer has not in any way interfered with the project, except for providing nonbinding comments to the final product. The entire text of this manual was written by Johan PE Karlberg. Marjorie A Speers provided considerable and essential comments on the contents and the first and subsequent drafts. A group of international human research protection experts mostly working in non-profit institutions or organisations - see Contributors for details - reviewed and provided important comments on the contents and final draft. It was solely created with the intention to promote human research protection of participants in clinical trials. This manual will be translated into numerous languages and is provided free of charge as an electronic file over the Internet (http://www.ClinicalTrialMagnifier.com) and offered in print for a fee. The objective beyond this project is to establish educational activities, developed around the manual, and jointly organised with leading academic institutions worldwide. |
| dose escalation study design: Adaptive Design Theory and Implementation Using SAS and R Mark Chang, 2014-12-01 Get Up to Speed on Many Types of Adaptive DesignsSince the publication of the first edition, there have been remarkable advances in the methodology and application of adaptive trials. Incorporating many of these new developments, Adaptive Design Theory and Implementation Using SAS and R, Second Edition offers a detailed framework to understand the |
| dose escalation study design: Broken Movement John W. Krakauer, S. Thomas Carmichael, 2022-06-07 An account of the neurobiology of motor recovery in the arm and hand after stroke by two experts in the field. Stroke is a leading cause of disability in adults and recovery is often difficult, with existing rehabilitation therapies largely ineffective. In Broken Movement, John Krakauer and S. Thomas Carmichael, both experts in the field, provide an account of the neurobiology of motor recovery in the arm and hand after stroke. They cover topics that range from behavior to physiology to cellular and molecular biology. Broken Movement is the only accessible single-volume work that covers motor control and motor learning as they apply to stroke recovery and combines them with motor cortical physiology and molecular biology. The authors cast a critical eye at current frameworks and practices, offer new recommendations for promoting recovery, and propose new research directions for the study of brain repair. Krakauer and Carmichael discuss such subjects as the behavioral phenotype of hand and arm paresis in human and non-human primates; the physiology and anatomy of the motor system after stroke; mechanisms of spontaneous recovery; the time course of early recovery; the challenges of chronic stroke; and pharmacological and stem cell therapies. They argue for a new approach in which patients are subjected to higher doses and intensities of rehabilitation in a more dynamic and enriching environment early after stroke. Finally they review the potential of four areas to improve motor recovery: video gaming and virtual reality, invasive brain stimulation, re-opening the sensitive period after stroke, and the application of precision medicine. |
| dose escalation study design: Textbook of Clinical Trials David Machin, Simon Day, Sylvan Green, 2007-01-11 Now published in its Second Edition, the Textbook of Clinical Trials offers detailed coverage of trial methodology in diverse areas of medicine in a single comprehensive volume. Praise for the First Edition: ... very useful as an introduction to clinical research, or for those planning specific studies within therapeutic or disease areas. BRITISH JOURNAL OF SURGERY, Vol. 92, No. 2, February 2005 The book’s main concept is to describe the impact of clinical trials on the practice of medicine. It separates the information by therapeutic area because the impact of clinical trials, the problems encountered, and the numbers of trials in existence vary tremendously from specialty to specialty. The sections provide a background to the disease area and general clinical trial methodology before concentrating on particular problems experienced in that area. Specific examples are used throughout to address these issues. The Textbook of Clinical Trials, Second Edition: Highlights the various ways clinical trials have influenced the practice of medicine in many therapeutic areas Describes the challenges posed by those conducting clinical trials over a range of medical specialities and allied fields Additional therapeutic areas are included in this Second Edition to fill gaps in the First Edition as the number and complexity of trials increases in this rapidly developing area Newly covered or updated in the Second Edition: general surgery, plastic surgery, aesthetic surgery, palliative care, primary care, anaesthesia and pain, transfusion, wound healing, maternal and perinatal health, early termination, organ transplants, ophthalmology, epilepsy, infectious disease, neuro-oncology, adrenal, thyroid and urological cancers, as well as a chapter on the Cochrane network An invaluable resource for pharmaceutical companies, the Textbook of Clinical Trials, Second Edition appeals to those working in contract research organizations, medical departments and in the area of public health and health science alike. |
| dose escalation study design: Halcion Committee on Halcion: An Assessment of Data Adequacy and Confidence, Division of Health Sciences Policy, Institute of Medicine, 1997-12-15 Regulatory agencies within the United States and the United Kingdom, among several other countries, have reviewed extensively the safety and efficacy of Halcion (triazolam)--a once commonly used hypnotic drug. Concerns began to emerge about the safety of Halcion when a Dutch physician reported a possible link between it and a syndrome that included such effects as depression, amnesia, hallucinations, and increased anxiety. In addition, in 1991 its manufacturer, Upjohn, noted that errors had been identified in a report of one of the clinical studies included in the original application for approval. Since then, the drug has been removed from the market in several countries, whereas in the United States and Canada, the drug's labeling has been modified to reduce the recommended dose and duration of treatment and to heighten awareness of possible side effects. Yet different data and analyses have resulted in conflicting messages that are difficult to reconcile and interpret. In response to a request from the Food and Drug Administration to resolve these controversial issues related to the safety and efficacy of Halcion, this IOM book assesses the adequacy of the drug's clinical trials; the quality and quantity of data on adverse reactions; overall confidence in the data on effectiveness, adverse events, and side effects at different doses; and whether additional studies are needed. |
| dose escalation study design: Novel Designs of Early Phase Trials for Cancer Therapeutics Shivaani Kummar, Chris Takimoto, 2018-05-26 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. |
| dose escalation study design: Anticancer Drug Development Bruce C. Baguley, David J. Kerr, 2001-11-17 Here in a single source is a complete spectrum of ideas on the development of new anticancer drugs. Containing concise reviews of multidisciplinary fields of research, this book offers a wealth of ideas on current and future molecular targets for drug design, including signal transduction, the cell division cycle, and programmed cell death. Detailed descriptions of sources for new drugs and methods for testing and clinical trial design are also provided. - One work that can be consulted for all aspects of anticancer drug development - Concise reviews of research fields, combined with practical scientific detail, written by internationally respected experts - A wealth of ideas on current and future molecular targets for drug design, including signal transduction, the cell division cycle, and programmed cell death - Detailed descriptions of the sources of new anticancer drugs, including combinatorial chemistry, phage display, and natural products - Discussion of how new drugs can be tested in preclinical systems, including the latest technology of robotic assay systems, cell culture, and experimental animal techniques - Hundreds of references that allow the reader to access relevant scientific and medical literature - Clear illustrations, some in color, that provide both understanding of the field and material for teaching |
| dose escalation study design: Making Better Drugs for Children with Cancer National Research Council, Institute of Medicine, National Cancer Policy Board, Committee on Shortening the Time Line for New Cancer Treatments, 2005-03-31 The successes that have been achieved in treating childhood cancers stand as beacons against the less dramatic improvements for adults with cancer. Progress began to accelerate in the 1960s and 1970s, as treatment regimens were built up, primarily by building combinations of chemotherapeutic drugs. However the near absence of research in pediatric cancer drug discovery threatens to halt the progress in childhood cancer treatment achieved during the past four decades. Making Better Drugs for Children with Cancer identifies the major issues to be addressed in developing new agents for childhood cancers, the gaps in research and development, and the steps that have been suggested to move the process forward. This report also makes a new proposal to capitalize on today's science to bring new treatments to children's cancers. |
| dose escalation study design: And Still I Rise Maya Angelou, 2011-08-17 Maya Angelou’s unforgettable collection of poetry lends its name to the documentary film about her life, And Still I Rise, as seen on PBS’s American Masters. Pretty women wonder where my secret lies. I’m not cute or built to suit a fashion model’s size But when I start to tell them, They think I’m telling lies. I say, It’s in the reach of my arms, The span of my hips, The stride of my step, The curl of my lips. I’m a woman Phenomenally. Phenomenal woman, That’s me. Thus begins “Phenomenal Woman,” just one of the beloved poems collected here in Maya Angelou’s third book of verse. These poems are powerful, distinctive, and fresh—and, as always, full of the lifting rhythms of love and remembering. And Still I Rise is written from the heart, a celebration of life as only Maya Angelou has discovered it. “It is true poetry she is writing,” M.F.K. Fisher has observed, “not just rhythm, the beat, rhymes. I find it very moving and at times beautiful. It has an innate purity about it, unquenchable dignity. . . . It is astounding, flabbergasting, to recognize it, in all the words I read every day and night . . . it gives me heart, to hear so clearly the caged bird singing and to understand her notes.” |
| dose escalation study design: Handbook of Anticancer Drug Development Daniel Budman, A. Hilary Calvert, Eric K. Rowinsky, 2003 Perhaps no area of pharmacology has progressed further or faster than that of anticancer drugs. With this concise and informative resource, you'll explore the full spectrum of anticancer drug evolution -- from research and development, through clinical trials, to licensure and utilization. |
| dose escalation study design: Mindfulness-oriented Recovery Enhancement for Addiction, Stress, and Pain Eric L. Garland, 2013 Human existence can be beset by a variety of negative mental states such that life seems devoid of meaning, but it can also be liberated--a meaningful life reclaimed and savored through cultivation of a higher kind of mind. This quality, mindfulness, refers to both a set of contemplative practices and certain distinct psychological states and traits, and it can be cultivated through intentional effort and training. In Mindfulness-Oriented Recovery Enhancement for Addiction, Stress, and Pain, Eric L. Garland presents an innovative program of intervention that can be put into practice by therapists working with people struggling with addiction and the conditions that underlie it. Unlike other substance abuse treatment modalities, which focus largely on relapse prevention, Mindfulness-Oriented Recovery Enhancement (MORE) concentrates on helping people to recover a sense of meaning and fulfillment in everyday life, embracing its pleasures and pain without avoiding challenges by turning to substance use. Along with chapters on the bipsychosocial model underlying MORE and the current state of research on mindfulness, this book includes a complete treatment manual laying out for clinicians, step by step, how to run MORE groups--including adaptations to address chronic pain and prescription opioid misuse-- and enhance the holistic recovery process for people striving to overcome addiction. With addiction a widespread and growing problem in our society, Mindfulness-Oriented Recovery Enhancement could not be more timely or needed. It integrates the latest research on addiction, cognitive neuroscience, positive psychology, and mindfulness into a practice that has garnered empirical support and holds the promise of release and fulfillment for those who suffer from addiction.--Publisher's website. |
Dose Escalation Study Design Example Record
The primary aim of the study is to establish the maximum-tolerated dose (MTD) of Ender-G in participants with cancer. The secondary aims are to describe the pharmacokinetics of Ender-G …
PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING …
Modeling of dose response, including Emax model. Optimal Design. PAD often helpful in guiding the dose escalation, but over-confidence may lead to inconclusive results in phase II.
Phase 1 clinical trials: Designs and considerations - Queen's U
Dose-escalation study to determine an acceptable level of dose-limiting toxicity (DLT) = MTD/RP2D
Phase I Clinical Trial Design - National Institutes of Health
phase I trial is designed as a dose-escalation study to determine the maximum tolerable dosage (MTD), that is, the maximum dose associated with an acceptable level of dose-limiting toxicity …
Designing and evaluating dose-escalation studies made easy: …
Bayesian dose-escalation design. Results: MoDEsT comes in two parts: a ‘Design’ module to explore design options and simulate their operating charac- teristics, and a ‘Conduct’ module to guide …
Optimizing First-in-Human Study Design with Predictive Dose …
A critical step in initiation of a First-In-Human (FIH) study for a novel therapeutic is determining the appropriate starting dose and dose range to appropriately define the pharmacokinetics (PK), …
A new pragmatic design for dose escalation in phase 1 clinical …
We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible.
Accelerated Titration Designs - National Institutes of Health
Simon et al [7] proposed a family of accelerated titration dose escalation designs. In their formulation all designs use 40% dose escalation steps. The dose escalation/de-escalation rules …
Protocol B7861002 A PHASE 1 DOSE ESCALATION STUDY …
dose, safety, pharmacokinetic and pharmacodynamic study of single-agent PF-06747143 in sequential dose levels of adult patients with refractory and/or relapsed AML in order to establish …
Establish the Maximum Tolerated Dose in Phase-I Trials using …
Dose escalation methods for phase-I oncology trials fall into two broad classes: the rule-based designs and the model-based designs.
Adaptive Design for Intra Patient Dose Escalation in Phase I …
When designing a phase I study, intrapatient dose escalation is reasonable and should be encouraged in order to minimize the number of patients exposed to subtherapeutic doses of …
PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING …
Modeling of dose response, including Emax model. Optimal Design. PAD often helpful in guiding the dose escalation, but over-confidence may lead to inconclusive results in phase II.
Guideline on strategies to identify and mitigate risks for first-in ...
• Applying a scientific rationale in the selection of the starting dose , for dose escalation and when defining the maximum exposure to be achieved (section 7); • Applying appropriate risk mitigating …
CLINICAL STUDY PROTOCOL PHASE 1/2 DOSE …
Methodology/Study Design: BVD-523-02 is an open-label, multicenter, Phase 1/2 study with a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). Part 1 – Dose-escalation …
Dose Escalation in Preclinical Toxicology and …
Sep 24, 2015 · What are we dosing and why? What do we need from our nonclinical formulations? How the requirements for nonclinical formulations change over the lifespan of a drug …
The design, preclinical study and phase I dose escalation plan …
Conclusions: The encouraging preclinical data supported a clinical trial starting with dose escalation at equivalent antibody doses of 0.72 mg/m2, 2.16 mg/m2, 5.4 mg/m2, 10.8 mg/ m2, 16.2mg/m2, …
Dose Escalation Study Design Fictional Manuscript
This single-group open label dose-escalation study of Ender-G enrolled participants with various cancer types from a single academic medical center in Bethesda, Maryland, in the United States.
Phase 1 Trial Design: Is 3 + 3 the Best? - SAGE Journals
Dose-Escalation Designs Phase 1 trials must prioritize safety while attempting to maintain efficiency. A typical dose-escalation phase 1 study selects a safe starting dose based on preclini-cal data …
CLINICAL STUDY PROTOCOL A Phase 1A Single Ascending …
Part B will be a multiple-ascending dose escalation design, to be run only after review of safety and pharmacokinetic data from Part A. In the single ascending dose study (Part A) at least 4 dose …
Protocol C4011001 A PHASE 1 DOSE ESCALATION AND …
The study contains 2 parts, single agent dose escalation (Part 1) followed by a dose expansion at the RP2D (Part 2). The overall study design is depicted in the schema (Section 1.2 in the …
Dose Escalation Study Design Example Record
The primary aim of the study is to establish the maximum-tolerated dose (MTD) of Ender-G in participants with cancer. The secondary aims are to describe the pharmacokinetics of Ender-G …
PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING …
Modeling of dose response, including Emax model. Optimal Design. PAD often helpful in guiding the dose escalation, but over-confidence may lead to inconclusive results in phase II.
Phase 1 clinical trials: Designs and considerations - Queen's U
Dose-escalation study to determine an acceptable level of dose-limiting toxicity (DLT) = MTD/RP2D
Phase I Clinical Trial Design - National Institutes of Health
phase I trial is designed as a dose-escalation study to determine the maximum tolerable dosage (MTD), that is, the maximum dose associated with an acceptable level of dose-limiting toxicity …
Designing and evaluating dose-escalation studies made easy: …
Bayesian dose-escalation design. Results: MoDEsT comes in two parts: a ‘Design’ module to explore design options and simulate their operating charac- teristics, and a ‘Conduct’ module …
Optimizing First-in-Human Study Design with Predictive …
A critical step in initiation of a First-In-Human (FIH) study for a novel therapeutic is determining the appropriate starting dose and dose range to appropriately define the pharmacokinetics (PK), …
A new pragmatic design for dose escalation in phase 1 …
We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible.
Accelerated Titration Designs - National Institutes of Health
Simon et al [7] proposed a family of accelerated titration dose escalation designs. In their formulation all designs use 40% dose escalation steps. The dose escalation/de-escalation …
Protocol B7861002 A PHASE 1 DOSE ESCALATION STUDY …
dose, safety, pharmacokinetic and pharmacodynamic study of single-agent PF-06747143 in sequential dose levels of adult patients with refractory and/or relapsed AML in order to …
Establish the Maximum Tolerated Dose in Phase-I Trials …
Dose escalation methods for phase-I oncology trials fall into two broad classes: the rule-based designs and the model-based designs.
Adaptive Design for Intra Patient Dose Escalation in Phase I …
When designing a phase I study, intrapatient dose escalation is reasonable and should be encouraged in order to minimize the number of patients exposed to subtherapeutic doses of …
PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING …
Modeling of dose response, including Emax model. Optimal Design. PAD often helpful in guiding the dose escalation, but over-confidence may lead to inconclusive results in phase II.
Guideline on strategies to identify and mitigate risks for first …
• Applying a scientific rationale in the selection of the starting dose , for dose escalation and when defining the maximum exposure to be achieved (section 7); • Applying appropriate risk …
CLINICAL STUDY PROTOCOL PHASE 1/2 DOSE-ESCALATION, …
Methodology/Study Design: BVD-523-02 is an open-label, multicenter, Phase 1/2 study with a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). Part 1 – Dose …
Dose Escalation in Preclinical Toxicology and …
Sep 24, 2015 · What are we dosing and why? What do we need from our nonclinical formulations? How the requirements for nonclinical formulations change over the lifespan of a …
The design, preclinical study and phase I dose escalation …
Conclusions: The encouraging preclinical data supported a clinical trial starting with dose escalation at equivalent antibody doses of 0.72 mg/m2, 2.16 mg/m2, 5.4 mg/m2, 10.8 mg/ m2, …
Dose Escalation Study Design Fictional Manuscript
This single-group open label dose-escalation study of Ender-G enrolled participants with various cancer types from a single academic medical center in Bethesda, Maryland, in the United States.
Phase 1 Trial Design: Is 3 + 3 the Best? - SAGE Journals
Dose-Escalation Designs Phase 1 trials must prioritize safety while attempting to maintain efficiency. A typical dose-escalation phase 1 study selects a safe starting dose based on …
CLINICAL STUDY PROTOCOL A Phase 1A Single Ascending …
Part B will be a multiple-ascending dose escalation design, to be run only after review of safety and pharmacokinetic data from Part A. In the single ascending dose study (Part A) at least 4 …
Protocol C4011001 A PHASE 1 DOSE ESCALATION AND …
The study contains 2 parts, single agent dose escalation (Part 1) followed by a dose expansion at the RP2D (Part 2). The overall study design is depicted in the schema (Section 1.2 in the …
