A Practical Guide to Designing Phase II Trials in Oncology
Statistics in Practice Series

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.

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