A Practical Guide to Designing Phase II Trials in Oncology: (Statistics in Practice)

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.

Table of Contents:
Contributors xv Foreword I xvii Elizabeth A. Eisenhauer Foreword II xix Roger A’Hern Preface xxi 1 Introduction 1 Sarah Brown, Julia Brown, Walter Gregory and Chris Twelves 1.1 The role of phase II trials in cancer 3 1.2 The importance of appropriate phase II trial design 5 1.3 Current use of phase II designs 6 1.4 Identifying appropriate phase II trial designs 7 1.5 Potential trial designs 9 1.6 Using the guidance to design your trial 10 2 Key Points for Consideration 12 Sarah Brown, Julia Brown, Marc Buyse, Walter Gregory, Mahesh Parmar and Chris Twelves 2.1 Stage 1 – Trial questions 14 2.1.1 Therapeutic considerations 14 2.1.2 Primary intention of trial 16 2.1.3 Number of experimental treatment arms 17 2.1.4 Primary outcome of interest 18 2.2 Stage 2 – Design components 18 2.2.1 Outcome measure and distribution 18 2.2.2 Randomisation 21 2.2.3 Design category 26 2.3 Stage 3 – Practicalities 33 2.3.1 Practical considerations 33 2.4 Summary 35 3 Designs for Single Experimental Therapies with a Single Arm 36 Sarah Brown 3.1 One-stage designs 36 3.1.1 Binary outcome measure 36 3.1.2 Continuous outcome measure 38 3.1.3 Multinomial outcome measure 39 3.1.4 Time-to-event outcome measure 40 3.1.5 Ratio of times to progression 40 3.2 Two-stage designs 41 3.2.1 Binary outcome measure 41 3.2.2 Continuous outcome measure 50 3.2.3 Multinomial outcome measure 50 3.2.4 Time-to-event outcome measure 53 3.2.5 Ratio of times to progression 54 3.3 Multi-stage designs 55 3.3.1 Binary outcome measure 55 3.3.2 Continuous outcome measure 59 3.3.3 Multinomial outcome measure 59 3.3.4 Time-to-event outcome measure 60 3.3.5 Ratio of times to progression 60 3.4 Continuous monitoring designs 60 3.4.1 Binary outcome measure 60 3.4.2 Continuous outcome measure 63 3.4.3 Multinomial outcome measure 63 3.4.4 Time-to-event outcome measure 63 3.4.5 Ratio of times to progression 64 3.5 Decision-theoretic designs 64 3.5.1 Binary outcome measure 64 3.5.2 Continuous outcome measure 65 3.5.3 Multinomial outcome measure 65 3.5.4 Time-to-event outcome measure 65 3.5.5 Ratio of times to progression 65 3.6 Three-outcome designs 65 3.6.1 Binary outcome measure 65 3.6.2 Continuous outcome measure 66 3.6.3 Multinomial outcome measure 66 3.6.4 Time-to-event outcome measure 66 3.6.5 Ratio of times to progression 67 3.7 Phase II/III designs 67 4 Designs for Single Experimental Therapies Including Randomisation 68 Sarah Brown 4.1 One-stage designs 68 4.1.1 Binary outcome measure 68 4.1.2 Continuous outcome measure 70 4.1.3 Multinomial outcome measure 70 4.1.4 Time-to-event outcome measure 70 4.1.5 Ratio of times to progression 72 4.2 Two-stage designs 72 4.2.1 Binary outcome measure 72 4.2.2 Continuous outcome measure 73 4.2.3 Multinomial outcome measure 74 4.2.4 Time-to-event outcome measure 75 4.2.5 Ratio of times to progression 75 4.3 Multi-stage designs 75 4.3.1 Binary outcome measure 75 4.3.2 Continuous outcome measure 75 4.3.3 Multinomial outcome measure 75 4.3.4 Time-to-event outcome measure 76 4.3.5 Ratio of times to progression 76 4.4 Continuous monitoring designs 76 4.4.1 Binary outcome measure 76 4.4.2 Continuous outcome measure 76 4.4.3 Multinomial outcome measure 76 4.4.4 Time-to-event outcome measure 76 4.4.5 Ratio of times to progression 76 4.5 Three-outcome designs 77 4.5.1 Binary outcome measure 77 4.5.2 Continuous outcome measure 77 4.5.3 Multinomial outcome measure 77 4.5.4 Time-to-event outcome measure 77 4.5.5 Ratio of times to progression 77 4.6 Phase II/III designs 77 4.6.1 Binary outcome measure 77 4.6.2 Continuous outcome measure 79 4.6.3 Multinomial outcome measure 80 4.6.4 Time-to-event outcome measure 81 4.6.5 Ratio of times to progression 81 4.7 Randomised discontinuation designs 82 4.7.1 Binary outcome measure 82 4.7.2 Continuous outcome measure 82 4.7.3 Multinomial outcome measure 82 4.7.4 Time-to-event outcome measure 82 4.7.5 Ratio of times to progression 82 5 Treatment Selection Designs 83 Sarah Brown 5.1 Including a control arm 84 5.1.1 One-stage designs 84 5.1.2 Two-stage designs 84 5.1.3 Multi-stage designs 88 5.1.4 Continuous monitoring designs 89 5.1.5 Decision-theoretic designs 89 5.1.6 Three-outcome designs 89 5.1.7 Phase II/III designs – same primary outcome measure at phase II and phase III 89 5.1.8 Phase II/III designs – different primary outcome measures at phase II and phase III 99 5.1.9 Randomised discontinuation designs 102 5.2 Not including a control arm 103 5.2.1 One-stage designs 103 5.2.2 Two-stage designs 106 5.2.3 Multi-stage designs 108 5.2.4 Continuous monitoring designs 109 5.2.5 Decision-theoretic designs 110 5.2.6 Three-outcome designs 110 5.2.7 Phase II/III designs – same primary outcome measure at phase II and phase III 110 5.2.8 Randomised discontinuation designs 111 6 Designs Incorporating Toxicity as a Primary Outcome 112 Sarah Brown 6.1 Including a control arm 112 6.1.1 One-stage designs 112 6.1.2 Two-stage designs 114 6.1.3 Multi-stage designs 115 6.2 Not including a control arm 117 6.2.1 One-stage designs 117 6.2.2 Two-stage designs 118 6.2.3 Multi-stage designs 122 6.2.4 Continuous monitoring designs 125 6.3 Toxicity alone 126 6.3.1 One stage 126 6.3.2 Continuous monitoring 127 6.4 Treatment selection based on activity and toxicity 128 6.4.1 Two-stage designs 128 6.4.2 Multi-stage designs 129 6.4.3 Continuous monitoring designs 129 7 Designs Evaluating Targeted Subgroups 131 Sarah Brown 7.1 One-stage designs 131 7.1.1 Binary outcome measure 131 7.2 Two-stage designs 132 7.2.1 Binary outcome measure 132 7.3 Multi-stage designs 135 7.3.1 Binary outcome measure 135 7.3.2 Time-to-event outcome measure 137 7.4 Continuous monitoring designs 138 7.4.1 Binary outcome measure 138 7.4.2 Time-to-event outcome measure 139 8 ‘Chemo-radio-sensitisation’ in Head and Neck Cancer 141 John Chester and Sarah Brown Stage 1 – Trial questions 141 Therapeutic considerations 141 Primary intention of trial 142 Number of experimental treatment arms 142 Primary outcome of interest 142 Stage 2 – Design components 142 Outcome measure and distribution 142 Randomisation 143 Design category 143 Possible designs 144 Stage 3 – Practicalities 146 Practical considerations for selecting between designs 146 Proposed trial design 148 Summary 150 9 Combination Chemotherapy in Second-line Treatment of Non-small Cell Lung Cancer 151 Ornella Belvedere and Sarah Brown Stage 1 – Trial questions 152 Therapeutic considerations 152 Primary intention of trial 152 Number of experimental treatment arms 152 Primary outcome of interest 152 Stage 2 – Design components 153 Outcome measure and distribution 153 Randomisation 153 Design category 153 Possible designs 154 Stage 3 – Practicalities 155 Practical considerations for selecting between designs 155 Proposed trial design 158 Summary 162 10 Selection by Biomarker in Prostate Cancer 163 Rick Kaplan and Sarah Brown Stage 1 – Trial questions 164 Therapeutic considerations 164 Primary intention of trial 164 Number of experimental treatment arms 164 Primary outcome of interest 164 Stage 2 – Design components 165 Outcome measure and distribution 165 Randomisation 165 Design category 166 Possible designs 167 Stage 3 – Practicalities 168 Practical considerations for selecting between designs 168 Proposed trial design 170 Summary 171 11 Dose Selection in Advanced Multiple Myeloma 174 Sarah Brown and Steve Schey Stage 1 – Trial questions 174 Therapeutic considerations 174 Primary intention of trial 175 Number of experimental arms 175 Primary outcome of interest 175 Stage 2 – Design components 176 Outcome measure and distribution 176 Randomisation 176 Design category 177 Possible designs 177 Stage 3 – Practicalities 178 Practical considerations for selecting between designs 178 Proposed trial design 181 Summary 182 12 Targeted Therapy for Advanced Colorectal Cancer 185 Matthew Seymour and Sarah Brown Stage 1 – Trial questions 185 Therapeutic considerations 185 Primary intention of trial 186 Number of experimental treatment arms 186 Primary outcome of interest 186 Stage 2 – Design components 187 Outcome measure and distribution 187 Randomisation 187 Design category 188 Possible designs 189 Stage 3 – Practicalities 190 Practical considerations for selecting between designs 190 Proposed trial design 191 Summary 194 13 Phase II Oncology Trials: Perspective from Industry 195 Anthony Rossini, Steven Green and William Mietlowski 13.1 Introduction 195 13.2 Commercial challenges, drivers and considerations 196 13.3 Selecting designs by strategy 197 13.3.1 Basic strategies addressed by phase II studies 198 13.3.2 Potential registration 198 13.3.3 Exploratory activity 203 13.3.4 Regimen selection 204 13.3.5 Phase II to Support Predicting Success in Phase IIi 206 13.3.6 Phase II safety trials 208 13.3.7 Prospective identification of target populations 209 13.4 Discussion 210 References 213 Index 227