Principles of Anticancer Drug Development (eBook)

Principles of Anticancer Drug Development 3
Blurb 5
Preface 7
Contents 9
Contributors 11
Part I 19
Chapter 1: Basic Biostatistics for the Clinical Trialist 20
1.1 Introduction 20
1.2 Example 20
1.3 Aims, Endpoints, and Data Analysis 21
1.4 Variable Types 22
1.4.1 Continuous Variables 22
1.4.2 Categorical Variables 24
1.4.3 Time-to-Event Variables 24
1.4.4 Variable Transformation 24
1.5 Data Description and Displays 25
1.5.1 Continuous Variables 25
1.5.2 Categorical Variables 28
1.5.3 Time-to-Event Variables 29
1.5.4 Confidence Intervals 30
1.5.5 Confidence Intervals for Means and Differences in Means 31
1.5.6 Confidence Intervals for Proportions and Comparisons of Proportions 32
1.5.7 Confidence Intervals for Time-to-Event Parameters 33
1.6 Hypothesis Testing 34
1.6.1 From Research Question to Statistical Hypothesis 34
1.6.2 Evaluating Evidence Through p-values 34
1.6.3 Types of Errors 37
1.7 Common One- and Two-Sample Tests 37
1.7.1 Comparing Proportions 37
1.7.2 Comparing Means 38
1.7.3 The Chi-Square Test 40
1.7.4 Fisher’s Exact Test 42
1.7.5 Testing Paired Data 42
1.7.6 Comparing Survival Times 43
1.8 How Many Subjects Do I Need? 44
1.8.1 Precision-Based Calculations 44
1.8.2 Test-Based Calculations 45
1.9 Multivariable Regression Analyses 47
1.9.1 Logistic Regression 48
1.9.2 Cox Proportional Hazards Regression 50
References 51
Chapter 2: Fundamental Concepts in Clinical Pharmacology 53
2.1 Introduction 53
2.2 Glossary 54
2.2.1 Pharmacokinetic Terms 54
2.2.2 Pharmacodynamic Terms 55
2.2.3 Modeling Terms 55
2.3 Sampling Schedule and Study Design 56
2.4 Patient Numbers and Sampling Intensity 58
2.5 What is the Goal of the PK Study? 59
2.6 Pharmacokinetics 60
2.7 Pharmacokinetic Models 65
2.7.1 Compartmental Modeling 65
2.7.1.1 One-Compartment Model 66
2.7.1.2 Multicompartment Models 68
2.7.2 Nonlinear Pharmacokinetics 70
2.7.3 Noncompartmental Pharmacokinetics 71
2.7.4 Physiologically Based Pharmacokinetic Models 72
2.7.5 Population Pharmacokinetics 76
References 77
Chapter 3: Bioanalytical Methods in Clinical Drug Development 79
3.1 Introduction 79
3.2 Methods for Sample Preparation 82
3.2.1 Total Drug Measurements 83
3.2.1.1 Protein Precipitation 83
3.2.1.2 Solid Phase Extraction 83
3.2.1.3 Liquid–Liquid Extraction 84
3.2.2 Unbound Drug Measurements 84
3.2.2.1 Equilibrium Dialysis 85
3.2.2.2 Ultrafiltration 85
3.2.2.3 Ultracentrifugation 85
3.2.2.4 Protein Precipitation 86
3.2.2.5 Microdialysis (Extracellular Fluid) 86
3.3 Methods for Sample Separation 88
3.3.1 Liquid Chromatography 88
3.3.1.1 Ultraviolet and Visible Spectroscopy 89
3.3.1.2 Fluorescence 90
3.3.1.3 Electrical Conductivity 90
3.3.1.4 Mass Spectrometry 90
3.3.2 Gas Chromatography 91
3.3.3 Atomic Spectroscopy 92
3.3.3.1 Atomic Absorption Spectroscopy 92
3.3.3.2 Inductively Coupled Plasma Mass Spectrometry 94
3.4 Validation Requirements 94
3.4.1 Range of Reliable Response, Linearity, and Calibration Curves 95
3.4.2 Selectivity or Specificity 96
3.4.3 Sensitivity 96
3.4.4 Accuracy 97
3.4.5 Reproducibility 99
3.4.6 Stability 99
3.4.7 Matrix Effect in LC–MS/MS Based Methods 101
3.4.8 Recovery 101
References 102
Part II 103
Chapter 4: Preclinical Models for Anticancer Drug Development 104
4.1 Introduction 104
4.1.1 Molecular and Chemical Descriptors of Successful Drugs 105
4.1.2 Empirical Versus Rational Discovery and Development Strategies 108
4.2 Methods for Large Volume Screening 110
4.2.1 Historical Perspective 110
4.2.2 Ancillary Needs in Developing a Screening Program 112
4.2.3 Types of “Large Volume” Screens 113
4.2.4 Managing “Positive” and “Negative” Screening Results 115
4.3 Methods for In Vivo Evaluation 117
4.3.1 Overview of In Vivo Testing Goals 117
4.3.2 Types of Mouse Models for Cancer Drug Evaluation 118
4.3.3 Clinical Correlation with In Vivo Screeningand Model Results 122
4.4 Summary and Conclusions 124
References 125
Part III 130
Chapter 5: Phase I Clinical Trials with Anticancer Agents 131
5.1 Introduction 131
5.2 Design Options and Dose Escalation 132
5.3 Selection of Starting Dose and Schedule 135
5.3.1 Preclinical Pharmacology Studies 135
5.3.2 Preclinical Toxicology Studies 136
5.3.3 Selection of the Phase I Starting Dose 136
5.3.3.1 Traditional Method 137
5.3.3.2 Modern Method 138
Step 1: NOAEL Determination 139
Step 2: HED Calculation 140
Step 3: Most Appropriate Species Selection 141
Step 4: Application of Safety Factor 141
Example Calculations for Converting Animal Doses to HEDs 142
5.3.3.3 Other Methods to Select the Starting Dose 142
5.4 Phase I Evaluation and Endpoints 142
5.4.1 Reporting of Toxicities 143
5.4.1.1 Adverse Events 143
5.4.1.2 Serious Adverse Events 144
5.4.2 Radiographic Evaluation 146
5.4.3 Correlative Studies 146
5.4.4 The Concept of Optimal Biologic Dose for Novel, Nontoxic Agents 147
5.5 Ethical Considerations of Phase I Oncology Trial 148
5.5.1 Therapeutic Intent 148
5.5.2 Risk–Benefit Ratio 149
5.5.2.1 Informed Consent 150
5.6 Conclusions 151
References 152
Chapter 6: Phase II Trials with Anticancer Agents 154
6.1 Introduction 154
6.2 Factors Influencing the Design of Phase II Trials 155
6.3 Endpoints in Phase II Trials 155
6.3.1 Objective Response Rate 155
6.3.2 Toxicity 156
6.3.3 Disease Progression 157
6.3.4 Other Endpoints 158
6.4 Phase II Trials Based on the Hypothesis-Testing Framework 158
6.4.1 Single-Stage Phase II Trials 158
6.4.2 Two-Stage Phase II Trials 159
6.4.3 Multistage Phase II Design 161
6.5 Randomized Phase II Trials 161
6.5.1 Randomized Phase II Trials to Provide a Concurrent “Comparator” Arm 161
6.5.2 Randomized Phase II Trials to Select from a Number of Experimental Arms 162
6.5.3 Randomized Phase II Trials as “Screening Trials” 163
6.5.4 Randomized Discontinuation Trials 163
6.5.5 Randomized Phase II/III Trials 164
6.5.6 Discussion Regarding Randomized Phase II Trials 164
6.6 Other Theoretical Frameworks for Phase II Trials 165
6.6.1 Bayesian Designs 165
6.6.2 Decision Theoretic Designs 166
6.6.3 Bivariate Analysis 166
6.7 Evolving Challenges in the Age of Targeted Therapies 167
6.8 Conclusions 168
References 171
Chapter 7: Phase III Clinical Trials with Anticancer Agents 175
7.1 Introduction 175
7.2 Population of a Phase III Clinical Trial 176
7.3 Randomization 177
7.3.1 Multiple Randomization 177
7.3.2 Stratification 178
7.4 General Trial Design 178
7.4.1 Endpoints in Phase III Clinical Trials 178
7.4.1.1 Primary Versus Secondary 178
7.4.1.2 Criteria for Measurement 178
7.4.1.3 Surrogate Endpoint 179
7.4.2 Masking 180
7.4.3 Multiple Arm Studies 181
7.4.4 Factorial Designs 181
7.4.5 Equivalence and Noninferiority Design 183
7.5 Biomarkers in Phase III Trials 183
7.6 Statistical Considerations 186
7.6.1 Hypothesis Testing and Confidence Intervals 186
7.6.2 Sample Size 187
7.6.3 Interim Analyses 188
7.7 Phase II/III Design 189
7.8 Independent Data Safety Monitoring Committee 190
7.9 Termination of a Clinical Trial Prior to the Final Analysis 190
7.10 Data Analysis and Reporting 191
7.10.1 Measures of Effectiveness in Results Reporting 191
7.10.1.1 Measurements for Proportions 192
Risk and Relative Risk 192
Relative Risk Reduction 192
Absolute Risk Reduction 192
Number Needed to be Treated 192
Odds Ratio 192
7.10.1.2 Measurement for Time-to-Event Outcomes 193
7.10.2 Univariable and Multivariable Testing 193
7.10.3 Subgroup Analyses 194
7.11 Transparency and Consistency in Clinical Trial Conduct and Reporting 195
7.11.1 Trial Registries 195
7.11.2 CONSORT Statement 197
7.12 Summary 197
References 197
Chapter 8: Pharmacokinetic Studies in Early Anticancer Drug Development 201
8.1 Introduction 201
8.2 Importance of Pharmacokinetic Studies in Oncology Drug Development 202
8.3 Establishing Pharmacokinetic–Pharmacodynamic Relationships 205
8.3.1 Preclinical Development 205
8.3.2 Clinical Development 205
8.3.2.1 Choice of a Starting Dose 205
8.3.2.2 Dose-Escalation Schemes 206
8.3.2.3 Obtaining Parameter Estimates 207
8.4 Sources of Pharmacokinetic Variability 207
8.4.1 Drug Scheduling and Administration Sequencing 207
8.4.2 Body Size and Body Composition 208
8.4.3 Age 209
8.4.3.1 Age-Related Absorption Changes 209
8.4.3.2 Age-Related Volume of Distribution Changes 210
8.4.3.3 Age-Related Changes in Renal Function 211
8.4.3.4 Age-Related Changes in Hepatic Metabolism 211
8.4.4 Pathophysiological Changes 212
8.4.4.1 Effects of Disease 212
8.4.4.2 Effects of Renal Impairment 212
8.4.4.3 Effects of Hepatic Impairment 213
8.4.4.4 Effects of Serum Proteins 215
8.4.5 Sex Dependence 215
8.4.6 Drug Interactions 216
8.4.6.1 Coadministration of Other Chemotherapeutic Drugs 216
8.4.6.2 Coadministration of Nonchemotherapeutic Drugs 216
8.4.6.3 Coadministration of Complementary and Alternative Medicine 218
8.4.7 Inherited Genetic Factors 220
8.5 Dose Adaptation Using Pharmacokinetic–Pharmacodynamic Principles 221
8.5.1 Therapeutic Drug Monitoring 221
8.5.2 Feedback-Controlled Dosing 221
8.6 Conclusions 222
References 223
Chapter 9: Pharmacodynamic Studies in Early Phase Drug Development 227
9.1 Introduction: The Role of Pharmacodynamic Biomarkers in Oncology and in Oncology Drug Development 227
9.2 Choosing the Right Biomarker for PD Studies of a Specific Drug 229
9.3 Choosing the Right Tissue for PD Studies: Tumor-Derived Tissue and Methodologies 231
9.3.1 Methods for Tissue Acquisition 232
9.3.1.1 Core Biopsies 232
9.3.1.2 Fine-Needle Aspirate Biopsy 232
9.3.1.3 Third-Space Collections (Ascites, Pleural Fluid) 234
9.3.2 Anatomical Sites to Be Biopsied 234
9.3.3 Tissue Heterogeneity 235
9.3.4 Technical Aspects of Processing and Preservation 236
9.3.4.1 Processing of Surgical and Core Biopsies 237
Frozen Tissues 237
Paraffin-Embedded Tissues for IHC 237
9.3.4.2 Cell Suspensions and FNAs: Special Handling Characteristics 238
DNA/mRNA Collection 238
Protein Analysis 238
Viable Cell Collection 239
9.3.5 Operational and Planning Aspects 239
9.3.6 Examples of Analytical Techniques for PD Endpoints 240
9.3.6.1 DNA Analysis 240
9.3.6.2 Messenger-RNA Analysis 240
9.3.6.3 Protein Analysis: Immunohistochemistry 241
9.4 Choosing the Right Tissue for PD Studies: Use of Surrogate Tissues (Nontumor/Normal Tissues) in PD Studies 244
9.4.1 Skin 244
9.4.2 Hair 246
9.4.3 Buccal Mucosa 247
9.4.4 White Blood Cells and Platelets 249
9.4.5 Circulating Ligands, Shed Receptors, and Endothelial Cells 251
9.5 Choosing the Right Tissue for PD Studies: Circulating Tumor Cells and Tumor Cell-Derived Materials 252
9.6 Incorporation of PD Markers Within Early Phase Clinical Trials 254
9.6.1 Proof of Drug Mechanism 254
9.6.2 Proof of Concept 257
9.6.3 Dose/Regimen Selection 259
9.6.4 Lead/Backup Compound Selection 261
9.6.5 Surrogate Marker of Clinical Benefit for Regulatory or Individual Patient Decision Making 261
9.7 Conclusions 262
References 262
Chapter 10: Prediction of Antitumor Response 269
10.1 Introduction 269
10.2 Tissue Collection Issues 270
10.3 Selection of Appropriate Assay 270
10.4 Centralized Laboratory 271
10.5 Statistical Approaches to Quality Control 272
10.5.1 Coefficient of Variation 272
10.5.2 Intraclass Correlation Coefficient and Variance Component Analysis 273
10.5.3 Case Study 275
10.6 Statistical Design of Clinical Trials with a Predictive Marker 275
10.6.1 Biomarker-Adaptive Threshold Design 276
10.6.2 Adaptive Signature Design 276
10.6.3 Power and Sample Size Analysis 277
10.7 Analysis and Reporting of Studies with Predictive Markers 279
10.7.1 Class Prediction 279
10.7.2 Compound Covariate Method 279
10.7.3 Weighted Flexible Compound Covariate Method 280
10.7.4 Random Forest Algorithm and Neural Networks 281
10.7.5 Leave-One-Out Cross-Validated Class Prediction Model 281
10.8 Conclusions 284
References 285
Chapter 11: Imaging Studies in Anticancer Drug Development 287
11.1 Introduction 287
11.1.1 Overview of Imaging and Cancer Therapy 287
11.1.2 Differences Between Imaging and Tissue/Blood Assays 288
11.1.3 Appropriate Roles 288
11.1.3.1 Early Drug Trials (Phase I/Early Phase II) 289
11.1.3.2 Late Phase II/III Drug Trials 289
11.1.3.3 Clinical Drug Therapy 290
11.2 Novel Imaging Methods for Drug Development:Overview of Imaging Modalities 290
11.2.1 Magnetic Resonance Imaging 290
11.2.2 Magnetic Resonance Spectroscopy 291
11.2.3 Radionuclide Imaging 292
11.2.4 Optical Imaging 293
11.2.5 Ultrasound 293
11.2.6 Other Imaging 294
11.3 Imaging to Define Targets and Select Patientsfor Clinical Trials 294
11.3.1 Overview 294
11.3.2 Examples of Imaging Target Expression 295
11.3.3 Imaging Resistance Factors 298
11.4 Imaging to Assess Early Pharmacodynamics/Response 299
11.4.1 Overview 299
11.4.2 Examples of Imaging Early Response 299
11.4.3 Examples of Imaging Pharmacodynamic Effect 302
11.4.4 Imaging as a Surrogate Endpoint? 302
11.5 Analysis and Reporting of Molecular Imaging Data 303
11.5.1 Standardization 303
11.5.2 Approach to Imaging Analysis 304
11.6 Summary and Conclusions 304
References 306
Part IV 315
Chapter 12: Role of the US Food and Drug Administration in Cancer Drug Development 316
12.1 Introduction 316
12.2 Role in Premarketing Development 318
12.2.1 What is an IND Application? 318
12.2.2 What is Needed for the IND Submission 321
12.2.2.1 Chemistry, Manufacturing, and Control 321
12.2.2.2 Nonclinical Pharmacology/Toxicology 322
Toxicology 323
Genotoxicity 323
Carcinogenicity 323
Safety Pharmacology 324
Immunogenicity 325
12.2.3 How to Fulfill IND Requirements 325
12.2.4 Responsibilities of the IND Holder 325
12.2.4.1 Required Safety Reporting 327
12.2.4.2 Annual Report 327
12.2.4.3 Informed Consent 328
12.2.4.4 Charging to Recover Cost 329
12.2.4.5 Clinical Trial Monitoring (Phase 1, 2 vs. 3) 329
12.2.4.6 Data Monitoring Committees 330
12.2.5 What Are the FDA’s Ongoing Responsibilities? 330
12.2.6 End of Phase 2 Meetings 331
12.2.7 Special Protocol Assessments 331
12.3 Role in Marketing and Postmarketing 331
12.3.1 NDA Classification and Content 332
12.3.2 General Efficacy Requirements 332
12.3.2.1 Efficacy Endpoints for Approval in Oncology 333
12.3.3 Postmarketing Considerations 334
12.4 Other Regulatory Considerations Throughout the Development Cycle 337
12.4.1 Agency Use of Consultants 337
12.4.1.1 Oncology Drugs Advisory Committee 337
12.4.2 Diagnostic Tests 338
12.4.3 Orphan Drug Program 339
12.4.4 Pediatric Initiatives 340
References 341
Part V 344
Chapter 13: Early Clinical Trials with Cytotoxic Agents 345
13.1 Introduction 345
13.2 Starting Dose and Schedule of Administration 346
13.3 Dose Escalation Methods 347
13.4 Correlative Studies in Clinical Trials with Cytotoxic Agents 348
13.5 Clinical Trials Combining Cytotoxic Agents 348
13.5.1 Starting Dose(s) 349
13.5.2 Dose Escalation 349
13.5.3 DLT Definition 350
13.5.4 Pharmacokinetics and Drug–Drug Interaction 351
13.6 Early Efficacy-Based Trials of Cytotoxic Agents 351
13.7 Conclusions 353
References 353
Chapter 14: Challenges and Successes in Developing Effective Anti-angiogenic Agents 356
14.1 Introduction 356
14.2 Angiogenesis and Its Mediators 359
14.2.1 Angiogenic Growth Factors 362
14.2.2 The Extracellular Matrix 362
14.2.3 The Immune System 363
14.2.4 Endothelial Cells and Endogenous Mediators of Angiogenesis 363
14.3 Preclincal Aspects: Assessing Anti-angiogenic Activity and Determining the Starting Dose and Schedule of Administration 364
14.3.1 Preclinical Screening Assays and Models Assessing Anti-angiogenic Activity 365
14.3.2 Determining the Starting Dose and Schedule of Administration 368
14.4 Clinical Aspects: Dose Escalation and Toxicity 369
14.4.1 Phase I Clinical Trial Methods and Design 369
14.4.2 Anti-angiogenic Agents and Toxicity 370
14.5 Efficacy-Oriented Anti-angiogenic Single Agent Clinical Trial Design 371
14.6 Specific Anti-angiogenic Agents in Clinical Trials 373
14.6.1 Matrix Metalloproteinase Inhibitors 373
14.6.2 Non-selective Anti-angiogenic Treatments 374
14.6.3 Antibody Therapies Against VEGF 374
14.6.4 Multi-targeted Receptor Tyrosine Kinase Inhibitors 377
14.6.4.1 Sorafenib 379
14.6.4.2 Sunitinib 380
14.6.4.3 Other Anti-angiogenic Multi-targeted Receptor Tyrosine Kinase Agents 381
14.6.5 Other Approaches to Angiogenesis Inhibition 382
14.6.5.1 Inhibitors of Endogenous Compounds or Receptors 382
14.6.5.2 Small-Molecule Vascular Targeting Agents 383
14.6.5.3 Viral Gene Therapy 384
14.7 Combination Therapy with Anti-angiogenics 386
14.7.1 Anti-angiogenics and Chemotherapy 386
14.7.2 Anti-angiogenics and Radiation Therapy 387
14.8 Correlative Anti-angiogenic Studies 388
14.8.1 Biologic Markers of Angiogenesis 390
14.8.2 Radiologic Markers of Angiogenesis 391
14.8.3 Mechanism-Based Toxicities and Clinical Markers of Anti-angiogenic Effects 392
14.9 Conclusion 393
References 394
Chapter 15: Targeted Therapeutics in Cancer Treatment 411
15.1 Introduction 411
15.2 Therapeutic Technologies 412
15.2.1 Antibodies 412
15.2.2 Tyrosine Kinase Inhibitors 415
15.2.3 Nucleic Acids 416
15.2.3.1 RNA Interference 417
15.2.3.2 Nucleic Acid Delivery Systems 417
15.3 Cell Cycle 418
15.4 Signal Transduction and Protein Kinases 424
15.4.1 Receptor Kinase Inhibition 425
15.4.1.1 Epidermal Growth Factor Receptor Family 425
Anti-EGFR Strategies 426
15.4.1.2 Insulin-Like Growth Factor-I Receptor 429
15.4.1.3 Hepatocyte Growth Factor and c-MET 431
HGF/c-MET Pathway Inhibition Strategies 432
15.4.1.4 Determinants of Response to RTK Therapy 434
15.4.2 Nonreceptor Kinase Inhibition 435
15.4.2.1 PI3Kinase/Akt/Mammalian Target of Rapamycin Pathway 435
15.4.2.2 mTOR-Targeting Agents 436
15.5 Mitogen-Activated Protein Kinase Family 439
15.5.1 Compounds in Development 440
15.5.1.1 RAS Inhibitors 440
15.5.1.2 Raf Inhibitors 442
15.5.1.3 MEK Inhibitors 443
15.6 SRC Kinase Inhibitors 445
15.7 Apoptosis 446
15.7.1 Prosurvival Signal Inhibition 447
15.7.1.1 BCL-2 447
15.7.2 Inhibitor of Apoptosis Protein 449
15.7.2.1 Survivin and XIAP 449
15.7.2.2 Peptidomimetics and Small Molecule Inhibitors of Prosurvival Proteins 450
15.7.2.3 Direct Proapoptosis Activation 451
15.8 Challenges in the Clinical Development of STI 452
15.8.1 Clinical Trials Design Issues 452
15.8.2 Patient Selection 453
15.8.3 Study Endpoints 454
15.8.4 Combination Therapy 455
References 456
Chapter 16: Cancer Chemoprevention 470
16.1 Introduction 470
16.2 Biologic Concepts 471
16.3 Population Selection 473
16.3.1 Cancer Risk Modeling 474
16.3.2 Convergent Trial Design 475
16.3.3 Hereditary Cancer Syndromes 476
16.4 Selection of Agents 477
16.4.1 Mechanism-Based Selection of Chemopreventive Agents 478
16.4.2 Molecular Biomarkers 479
16.4.3 Combination Strategies 480
16.4.4 Chemopreventive Agents in Infection-RelatedCancers and Vaccines 480
16.5 Endpoint Selection and Optimizing Risk–Benefit 481
16.5.1 Definitive and Intermediate Endpoints 482
16.5.2 Optimizing the Risk–Benefit Ratio 483
16.6 Conclusions 484
References 484
Chapter 17: Combined Modality Therapy in Cancer Management 489
17.1 Introduction 489
17.2 A Brief Explanation of Radiation Therapy Techniques and Modalities 490
17.2.1 Radiation Treatment Planning 490
17.2.2 Biological Basis of Radiation Therapy as It Pertainsto Combined Modality Therapy 492
17.3 Rationale for Combined Chemotherapy and Radiation 494
17.4 Examples of Combined Modality Success 505
17.4.1 Head and Neck Cancer 505
17.4.2 Nonsmall Cell Lung Cancer 508
17.4.3 Cervical Cancer 510
17.5 Esophageal Cancer 512
17.6 Conclusions 514
References 514
Chapter 18: Cancer Vaccines 524
18.1 Introduction 524
18.2 Features of the Immune System That Are Required for Successful Cancer Immunotherapy 525
18.2.1 Tumors Use Multiple Mechanisms To Evade Immune Recognition 525
18.2.1.1 Local Processes 525
18.2.1.2 Systemic Processes 526
18.3 Immunotherapy Clinical Trials 528
18.3.1 Antigen-Based Vaccines 530
18.3.2 Whole Tumor Cell Vaccines 532
18.4 New Immunotherapy Targets 533
18.4.1 Targeting Immune Checkpoints 534
18.4.2 Future Expectations 534
References 535
Chapter 19: Optimising the Development of Antibodies as Treatment for Cancer 539
19.1 Introduction 539
19.2 Antibody Structure and Function 539
19.3 Mechanisms of Action 540
19.3.1 Indirect 540
19.3.1.1 Antibody-Dependent Cell Cytotoxicity 540
19.3.1.2 Complement-Dependent Cytotoxicity 541
19.3.2 Direct 541
19.3.2.1 Cell Surface Receptor Antibodies 541
19.3.2.2 Neutralising Antibodies 541
19.3.2.3 Apoptosis Inducing Antibodies 541
19.3.2.4 Immune Modulation 542
19.3.2.5 Other Strategies 542
19.4 Target Validation 542
19.5 Antibody Technology: Murine, Chimeric, Humanised, and Fully Human Antibodies 542
19.6 Classes of Antibodies 544
19.6.1 Selected Unconjugated Antibodies Currently in Clinical Use 544
19.6.1.1 Rituximab 544
19.6.1.2 Bevacizumab 544
19.6.1.3 Trastuzumab 545
19.6.1.4 Cetuximab 545
19.6.1.5 Panitumumab 546
19.6.1.6 Alemtuzumab 546
19.7 Differences Between Small Molecules and Antibodies 546
19.8 Pharmacokinetics of Antibodies 546
19.9 Potential Toxicities 548
19.10 Preclinical Development: Animal–Human Model Transitions 549
19.11 TGN1412: A Cautionary Tale 549
19.12 Phase I Trials 551
19.12.1 Dose Selection 551
19.12.2 Staggering of Treatment of Patients 552
19.12.3 Schedule Selection 552
19.12.4 Selection of Patients 553
19.12.5 Trial Conduct 553
19.12.6 Dose Escalation 553
19.12.7 Pharmacokinetic Sampling 554
19.12.8 Pharmacodynamic Sampling to Biopsy or Not to Biopsy? 554
19.12.9 Combinations with Cytotoxic Chemotherapy or Radiotherapy 555
19.12.10 Combinations with Other Targeted Agents 555
19.12.11 Optimising Transition from Phase I to Phase II: The “Seamless” Transition 555
19.13 Phase II and III Trials 556
19.13.1 Endpoints and Study Design 556
19.13.2 Other Endpoint and Design Considerations 557
19.13.3 Selection of Recommended Phase II Dose 557
19.13.4 Selection of Patient Population 557
19.13.5 Moving from the Metastatic to the Adjuvant Setting 558
19.13.6 Single Agent Versus Combination with Chemotherapy 558
19.14 Emerging Technologies: Conjugated Antibodies (Immunoconjugates) 559
19.14.1 Drug-Immunoconjugates 560
19.14.2 Radio-Immunoconjugates 560
19.14.3 Immunotoxin Conjugates 561
19.15 Other Modulations of Antibody Function 561
19.15.1 Multivalent Antibodies 561
19.15.2 Antibody Fragments 562
19.15.3 Intrabodies 562
19.15.4 Modulation of Immunogenicity 562
19.15.4.1 Enhanced ADCC 562
19.15.4.2 Modulation of CDC 563
19.15.4.3 Modulation of Other Immune Components 563
19.16 Conclusions and Future Directions 564
References 564
Chapter 20: Oligonucleotide Therapeutics 572
20.1 Introduction 572
20.2 Clinical Trials of Oblimersen 574
20.2.1 Phase III Trial of Oblimersen in Chronic Lymphocytic Leukemia 574
20.2.2 Bcl-2 Silencing and Chemosensitization 576
20.2.3 Clinical Trials in Advanced Melanoma 577
20.2.4 Other Trials of Oblimersen 579
20.3 OGX-011 581
20.4 AP 12009 582
20.5 Affinitak 583
20.6 Conclusions 583
20.7 RNAi and siRNAs 583
References 585
Chapter 21: Anticancer Drug Development in Pediatric Patients 591
21.1 Introduction 591
21.2 Historical Perspective 591
21.3 The Difference Between Children and Adults 593
21.4 Drug Development in Pediatrics 595
21.5 The Role of Combination Studies 597
21.6 Conclusion 600
References 600
Chapter 22: Clinical Trials in Special Populations 604
22.1 Introduction 604
22.2 Organ Dysfunction 604
22.3 FDA Regulatory Guidance 606
22.4 Pharmacologic Outcomes vs. Toxicity 607
22.5 Hepatic Impairment 607
22.6 Renal Dysfunction 614
22.6.1 Measuring Renal Failure 615
22.7 Pharmacokinetics and Pharmacodynamics in Organ Dysfunction 617
22.8 The Dose Escalation Process 619
22.9 Another Challenge: The Elderly 619
22.10 The Pediatric Clinical Trial: An Additional Challenge 621
22.11 Conclusions 625
References 625
Part VI 630
Chapter 23: NCI-Sponsored Clinical Trials 631
23.1 Introduction 631
23.2 Agent Discovery and Development 633
23.2.1 The Drug Development Group 633
23.2.2 The Developmental Therapeutics Program: Organization and Resources 634
23.2.3 Programs to Assist Academics and Industry in Preclinical Drug Development Efforts 640
23.2.3.1 Rapid Access to NCI Discovery Resources Program 640
23.2.3.2 Rapid Access to Intervention Development Program 641
23.2.3.3 National Cooperative Drug Discovery Group Program 642
23.2.3.4 International Cooperative Biodiversity Groups Program 642
23.2.3.5 Rapid Access to Preventive Intervention and Development Program 642
23.3 Clinical Therapeutics Development and Resources 643
23.3.1 The Cancer Therapy Evaluation Program: Organization and Structure 644
23.3.1.1 Clinical Grants and Contracts Branch 645
23.3.1.2 Clinical Investigations Branch 646
23.3.1.3 Clinical Trials Monitoring Branch 646
23.3.1.4 Investigational Drug Branch 646
23.3.1.5 Pharmaceutical Management Branch 647
23.3.1.6 Regulatory Affairs Branch 647
23.3.1.7 Protocol and Information Office 647
23.3.2 CTEP-Sponsored Clinical Development of Investigational Agents and Resources 647
23.3.2.1 Clinical Trials Solicitations and Letters of Intent for Early Clinical Trials 648
23.3.2.2 Protocol Submission and Review 649
23.3.2.3 IND Submission 649
23.3.2.4 Data Reporting 650
23.3.2.5 Safety Data Reporting 650
23.3.2.6 Data and Safety Monitoring 651
23.3.3 Phase 3 Treatment Trials 652
23.4 Conclusion 655
References 655
Index 658