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
