Garrett-Mayer / Hidalgo Principles of Anticancer Drug Development
1. Auflage 2010
ISBN: 978-1-4419-7358-0
Verlag: Springer US
Format: PDF
Kopierschutz: 1 - PDF Watermark
E-Book, Englisch, 674 Seiten, eBook
Reihe: Cancer Drug Discovery and Development
ISBN: 978-1-4419-7358-0
Verlag: Springer US
Format: PDF
Kopierschutz: 1 - PDF Watermark
A practical guide to the design, conduction, analysis and reporting of clinical trials with anticancer drugs.
Zielgruppe
Research
Weitere Infos & Material
1;Principles of Anticancer Drug Development;3
1.1;Blurb;5
1.2;Preface;7
1.3;Contents;9
1.4;Contributors;11
1.5;Part I;19
1.5.1;Chapter 1: Basic Biostatistics for the Clinical Trialist;20
1.5.1.1;1.1 Introduction;20
1.5.1.2;1.2 Example;20
1.5.1.3;1.3 Aims, Endpoints, and Data Analysis;21
1.5.1.4;1.4 Variable Types;22
1.5.1.4.1;1.4.1 Continuous Variables;22
1.5.1.4.2;1.4.2 Categorical Variables;24
1.5.1.4.3;1.4.3 Time-to-Event Variables;24
1.5.1.4.4;1.4.4 Variable Transformation;24
1.5.1.5;1.5 Data Description and Displays;25
1.5.1.5.1;1.5.1 Continuous Variables;25
1.5.1.5.2;1.5.2 Categorical Variables;28
1.5.1.5.3;1.5.3 Time-to-Event Variables;29
1.5.1.5.4;1.5.4 Confidence Intervals;30
1.5.1.5.5;1.5.5 Confidence Intervals for Means and Differences in Means;31
1.5.1.5.6;1.5.6 Confidence Intervals for Proportions and Comparisons of Proportions;32
1.5.1.5.7;1.5.7 Confidence Intervals for Time-to-Event Parameters;33
1.5.1.6;1.6 Hypothesis Testing;34
1.5.1.6.1;1.6.1 From Research Question to Statistical Hypothesis;34
1.5.1.6.2;1.6.2 Evaluating Evidence Through p-values;34
1.5.1.6.3;1.6.3 Types of Errors;37
1.5.1.7;1.7 Common One- and Two-Sample Tests;37
1.5.1.7.1;1.7.1 Comparing Proportions;37
1.5.1.7.2;1.7.2 Comparing Means;38
1.5.1.7.3;1.7.3 The Chi-Square Test;40
1.5.1.7.4;1.7.4 Fisher’s Exact Test;42
1.5.1.7.5;1.7.5 Testing Paired Data;42
1.5.1.7.6;1.7.6 Comparing Survival Times;43
1.5.1.8;1.8 How Many Subjects Do I Need?;44
1.5.1.8.1;1.8.1 Precision-Based Calculations;44
1.5.1.8.2;1.8.2 Test-Based Calculations;45
1.5.1.9;1.9 Multivariable Regression Analyses;47
1.5.1.9.1;1.9.1 Logistic Regression;48
1.5.1.9.2;1.9.2 Cox Proportional Hazards Regression;50
1.5.1.10;References;51
1.5.2;Chapter 2: Fundamental Concepts in Clinical Pharmacology;53
1.5.2.1;2.1 Introduction;53
1.5.2.2;2.2 Glossary;54
1.5.2.2.1;2.2.1 Pharmacokinetic Terms;54
1.5.2.2.2;2.2.2 Pharmacodynamic Terms;55
1.5.2.2.3;2.2.3 Modeling Terms;55
1.5.2.3;2.3 Sampling Schedule and Study Design;56
1.5.2.4;2.4 Patient Numbers and Sampling Intensity;58
1.5.2.5;2.5 What is the Goal of the PK Study?;59
1.5.2.6;2.6 Pharmacokinetics;60
1.5.2.7;2.7 Pharmacokinetic Models;65
1.5.2.7.1;2.7.1 Compartmental Modeling;65
1.5.2.7.1.1;2.7.1.1 One-Compartment Model;66
1.5.2.7.1.2;2.7.1.2 Multicompartment Models;68
1.5.2.7.2;2.7.2 Nonlinear Pharmacokinetics;70
1.5.2.7.3;2.7.3 Noncompartmental Pharmacokinetics;71
1.5.2.7.4;2.7.4 Physiologically Based Pharmacokinetic Models;72
1.5.2.7.5;2.7.5 Population Pharmacokinetics;76
1.5.2.8;References;77
1.5.3;Chapter 3: Bioanalytical Methods in Clinical Drug Development;79
1.5.3.1;3.1 Introduction;79
1.5.3.2;3.2 Methods for Sample Preparation;82
1.5.3.2.1;3.2.1 Total Drug Measurements;83
1.5.3.2.1.1;3.2.1.1 Protein Precipitation;83
1.5.3.2.1.2;3.2.1.2 Solid Phase Extraction;83
1.5.3.2.1.3;3.2.1.3 Liquid–Liquid Extraction;84
1.5.3.2.2;3.2.2 Unbound Drug Measurements;84
1.5.3.2.2.1;3.2.2.1 Equilibrium Dialysis;85
1.5.3.2.2.2;3.2.2.2 Ultrafiltration;85
1.5.3.2.2.3;3.2.2.3 Ultracentrifugation;85
1.5.3.2.2.4;3.2.2.4 Protein Precipitation;86
1.5.3.2.2.5;3.2.2.5 Microdialysis (Extracellular Fluid);86
1.5.3.3;3.3 Methods for Sample Separation;88
1.5.3.3.1;3.3.1 Liquid Chromatography;88
1.5.3.3.1.1;3.3.1.1 Ultraviolet and Visible Spectroscopy;89
1.5.3.3.1.2;3.3.1.2 Fluorescence;90
1.5.3.3.1.3;3.3.1.3 Electrical Conductivity;90
1.5.3.3.1.4;3.3.1.4 Mass Spectrometry;90
1.5.3.3.2;3.3.2 Gas Chromatography;91
1.5.3.3.3;3.3.3 Atomic Spectroscopy;92
1.5.3.3.3.1;3.3.3.1 Atomic Absorption Spectroscopy;92
1.5.3.3.3.2;3.3.3.2 Inductively Coupled Plasma Mass Spectrometry;94
1.5.3.4;3.4 Validation Requirements;94
1.5.3.4.1;3.4.1 Range of Reliable Response, Linearity, and Calibration Curves;95
1.5.3.4.2;3.4.2 Selectivity or Specificity;96
1.5.3.4.3;3.4.3 Sensitivity;96
1.5.3.4.4;3.4.4 Accuracy;97
1.5.3.4.5;3.4.5 Reproducibility;99
1.5.3.4.6;3.4.6 Stability;99
1.5.3.4.7;3.4.7 Matrix Effect in LC–MS/MS Based Methods;101
1.5.3.4.8;3.4.8 Recovery;101
1.5.3.5;References;102
1.6;Part II;103
1.6.1;Chapter 4: Preclinical Models for Anticancer Drug Development;104
1.6.1.1;4.1 Introduction;104
1.6.1.1.1;4.1.1 Molecular and Chemical Descriptors of Successful Drugs;105
1.6.1.1.2;4.1.2 Empirical Versus Rational Discovery and Development Strategies;108
1.6.1.2;4.2 Methods for Large Volume Screening;110
1.6.1.2.1;4.2.1 Historical Perspective;110
1.6.1.2.2;4.2.2 Ancillary Needs in Developing a Screening Program;112
1.6.1.2.3;4.2.3 Types of “Large Volume” Screens;113
1.6.1.2.4;4.2.4 Managing “Positive” and “Negative” Screening Results;115
1.6.1.3;4.3 Methods for In Vivo Evaluation;117
1.6.1.3.1;4.3.1 Overview of In Vivo Testing Goals;117
1.6.1.3.2;4.3.2 Types of Mouse Models for Cancer Drug Evaluation;118
1.6.1.3.3;4.3.3 Clinical Correlation with In Vivo Screeningand Model Results;122
1.6.1.4;4.4 Summary and Conclusions;124
1.6.1.5;References;125
1.7;Part III;130
1.7.1;Chapter 5: Phase I Clinical Trials with Anticancer Agents;131
1.7.1.1;5.1 Introduction;131
1.7.1.2;5.2 Design Options and Dose Escalation;132
1.7.1.3;5.3 Selection of Starting Dose and Schedule;135
1.7.1.3.1;5.3.1 Preclinical Pharmacology Studies;135
1.7.1.3.2;5.3.2 Preclinical Toxicology Studies;136
1.7.1.3.3;5.3.3 Selection of the Phase I Starting Dose;136
1.7.1.3.3.1;5.3.3.1 Traditional Method;137
1.7.1.3.3.2;5.3.3.2 Modern Method;138
1.7.1.3.3.2.1;Step 1: NOAEL Determination;139
1.7.1.3.3.2.2;Step 2: HED Calculation;140
1.7.1.3.3.2.3;Step 3: Most Appropriate Species Selection;141
1.7.1.3.3.2.4;Step 4: Application of Safety Factor;141
1.7.1.3.3.2.5;Example Calculations for Converting Animal Doses to HEDs;142
1.7.1.3.3.3;5.3.3.3 Other Methods to Select the Starting Dose;142
1.7.1.4;5.4 Phase I Evaluation and Endpoints;142
1.7.1.4.1;5.4.1 Reporting of Toxicities;143
1.7.1.4.1.1;5.4.1.1 Adverse Events;143
1.7.1.4.1.2;5.4.1.2 Serious Adverse Events;144
1.7.1.4.2;5.4.2 Radiographic Evaluation;146
1.7.1.4.3;5.4.3 Correlative Studies;146
1.7.1.4.4;5.4.4 The Concept of Optimal Biologic Dose for Novel, Nontoxic Agents;147
1.7.1.5;5.5 Ethical Considerations of Phase I Oncology Trial;148
1.7.1.5.1;5.5.1 Therapeutic Intent;148
1.7.1.5.2;5.5.2 Risk–Benefit Ratio;149
1.7.1.5.2.1;5.5.2.1 Informed Consent;150
1.7.1.6;5.6 Conclusions;151
1.7.1.7;References;152
1.7.2;Chapter 6: Phase II Trials with Anticancer Agents;154
1.7.2.1;6.1 Introduction;154
1.7.2.2;6.2 Factors Influencing the Design of Phase II Trials;155
1.7.2.3;6.3 Endpoints in Phase II Trials;155
1.7.2.3.1;6.3.1 Objective Response Rate;155
1.7.2.3.2;6.3.2 Toxicity;156
1.7.2.3.3;6.3.3 Disease Progression;157
1.7.2.3.4;6.3.4 Other Endpoints;158
1.7.2.4;6.4 Phase II Trials Based on the Hypothesis-Testing Framework;158
1.7.2.4.1;6.4.1 Single-Stage Phase II Trials;158
1.7.2.4.2;6.4.2 Two-Stage Phase II Trials;159
1.7.2.4.3;6.4.3 Multistage Phase II Design;161
1.7.2.5;6.5 Randomized Phase II Trials;161
1.7.2.5.1;6.5.1 Randomized Phase II Trials to Provide a Concurrent “Comparator” Arm;161
1.7.2.5.2;6.5.2 Randomized Phase II Trials to Select from a Number of Experimental Arms;162
1.7.2.5.3;6.5.3 Randomized Phase II Trials as “Screening Trials”;163
1.7.2.5.4;6.5.4 Randomized Discontinuation Trials;163
1.7.2.5.5;6.5.5 Randomized Phase II/III Trials;164
1.7.2.5.6;6.5.6 Discussion Regarding Randomized Phase II Trials;164
1.7.2.6;6.6 Other Theoretical Frameworks for Phase II Trials;165
1.7.2.6.1;6.6.1 Bayesian Designs;165
1.7.2.6.2;6.6.2 Decision Theoretic Designs;166
1.7.2.6.3;6.6.3 Bivariate Analysis;166
1.7.2.7;6.7 Evolving Challenges in the Age of Targeted Therapies;167
1.7.2.8;6.8 Conclusions;168
1.7.2.9;References;171
1.7.3;Chapter 7: Phase III Clinical Trials with Anticancer Agents;175
1.7.3.1;7.1 Introduction;175
1.7.3.2;7.2 Population of a Phase III Clinical Trial;176
1.7.3.3;7.3 Randomization;177
1.7.3.3.1;7.3.1 Multiple Randomization;177
1.7.3.3.2;7.3.2 Stratification;178
1.7.3.4;7.4 General Trial Design;178
1.7.3.4.1;7.4.1 Endpoints in Phase III Clinical Trials;178
1.7.3.4.1.1;7.4.1.1 Primary Versus Secondary;178
1.7.3.4.1.2;7.4.1.2 Criteria for Measurement;178
1.7.3.4.1.3;7.4.1.3 Surrogate Endpoint;179
1.7.3.4.2;7.4.2 Masking;180
1.7.3.4.3;7.4.3 Multiple Arm Studies;181
1.7.3.4.4;7.4.4 Factorial Designs;181
1.7.3.4.5;7.4.5 Equivalence and Noninferiority Design;183
1.7.3.5;7.5 Biomarkers in Phase III Trials;183
1.7.3.6;7.6 Statistical Considerations;186
1.7.3.6.1;7.6.1 Hypothesis Testing and Confidence Intervals;186
1.7.3.6.2;7.6.2 Sample Size;187
1.7.3.6.3;7.6.3 Interim Analyses;188
1.7.3.7;7.7 Phase II/III Design;189
1.7.3.8;7.8 Independent Data Safety Monitoring Committee;190
1.7.3.9;7.9 Termination of a Clinical Trial Prior to the Final Analysis;190
1.7.3.10;7.10 Data Analysis and Reporting;191
1.7.3.10.1;7.10.1 Measures of Effectiveness in Results Reporting;191
1.7.3.10.1.1;7.10.1.1 Measurements for Proportions;192
1.7.3.10.1.1.1;Risk and Relative Risk;192
1.7.3.10.1.1.2;Relative Risk Reduction;192
1.7.3.10.1.1.3;Absolute Risk Reduction;192
1.7.3.10.1.1.4;Number Needed to be Treated;192
1.7.3.10.1.1.5;Odds Ratio;192
1.7.3.10.1.2;7.10.1.2 Measurement for Time-to-Event Outcomes;193
1.7.3.10.2;7.10.2 Univariable and Multivariable Testing;193
1.7.3.10.3;7.10.3 Subgroup Analyses;194
1.7.3.11;7.11 Transparency and Consistency in Clinical Trial Conduct and Reporting;195
1.7.3.11.1;7.11.1 Trial Registries;195
1.7.3.11.2;7.11.2 CONSORT Statement;197
1.7.3.12;7.12 Summary;197
1.7.3.13;References;197
1.7.4;Chapter 8: Pharmacokinetic Studies in Early Anticancer Drug Development;201
1.7.4.1;8.1 Introduction;201
1.7.4.2;8.2 Importance of Pharmacokinetic Studies in Oncology Drug Development;202
1.7.4.3;8.3 Establishing Pharmacokinetic–Pharmacodynamic Relationships;205
1.7.4.3.1;8.3.1 Preclinical Development;205
1.7.4.3.2;8.3.2 Clinical Development;205
1.7.4.3.2.1;8.3.2.1 Choice of a Starting Dose;205
1.7.4.3.2.2;8.3.2.2 Dose-Escalation Schemes;206
1.7.4.3.2.3;8.3.2.3 Obtaining Parameter Estimates;207
1.7.4.4;8.4 Sources of Pharmacokinetic Variability;207
1.7.4.4.1;8.4.1 Drug Scheduling and Administration Sequencing;207
1.7.4.4.2;8.4.2 Body Size and Body Composition;208
1.7.4.4.3;8.4.3 Age;209
1.7.4.4.3.1;8.4.3.1 Age-Related Absorption Changes;209
1.7.4.4.3.2;8.4.3.2 Age-Related Volume of Distribution Changes;210
1.7.4.4.3.3;8.4.3.3 Age-Related Changes in Renal Function;211
1.7.4.4.3.4;8.4.3.4 Age-Related Changes in Hepatic Metabolism;211
1.7.4.4.4;8.4.4 Pathophysiological Changes;212
1.7.4.4.4.1;8.4.4.1 Effects of Disease;212
1.7.4.4.4.2;8.4.4.2 Effects of Renal Impairment;212
1.7.4.4.4.3;8.4.4.3 Effects of Hepatic Impairment;213
1.7.4.4.4.4;8.4.4.4 Effects of Serum Proteins;215
1.7.4.4.5;8.4.5 Sex Dependence;215
1.7.4.4.6;8.4.6 Drug Interactions;216
1.7.4.4.6.1;8.4.6.1 Coadministration of Other Chemotherapeutic Drugs;216
1.7.4.4.6.2;8.4.6.2 Coadministration of Nonchemotherapeutic Drugs;216
1.7.4.4.6.3;8.4.6.3 Coadministration of Complementary and Alternative Medicine;218
1.7.4.4.7;8.4.7 Inherited Genetic Factors;220
1.7.4.5;8.5 Dose Adaptation Using Pharmacokinetic–Pharmacodynamic Principles;221
1.7.4.5.1;8.5.1 Therapeutic Drug Monitoring;221
1.7.4.5.2;8.5.2 Feedback-Controlled Dosing;221
1.7.4.6;8.6 Conclusions;222
1.7.4.7;References;223
1.7.5;Chapter 9: Pharmacodynamic Studies in Early Phase Drug Development;227
1.7.5.1;9.1 Introduction: The Role of Pharmacodynamic Biomarkers in Oncology and in Oncology Drug Development;227
1.7.5.2;9.2 Choosing the Right Biomarker for PD Studies of a Specific Drug;229
1.7.5.3;9.3 Choosing the Right Tissue for PD Studies: Tumor-Derived Tissue and Methodologies;231
1.7.5.3.1;9.3.1 Methods for Tissue Acquisition;232
1.7.5.3.1.1;9.3.1.1 Core Biopsies;232
1.7.5.3.1.2;9.3.1.2 Fine-Needle Aspirate Biopsy;232
1.7.5.3.1.3;9.3.1.3 Third-Space Collections (Ascites, Pleural Fluid);234
1.7.5.3.2;9.3.2 Anatomical Sites to Be Biopsied;234
1.7.5.3.3;9.3.3 Tissue Heterogeneity;235
1.7.5.3.4;9.3.4 Technical Aspects of Processing and Preservation;236
1.7.5.3.4.1;9.3.4.1 Processing of Surgical and Core Biopsies;237
1.7.5.3.4.1.1;Frozen Tissues;237
1.7.5.3.4.1.2;Paraffin-Embedded Tissues for IHC;237
1.7.5.3.4.2;9.3.4.2 Cell Suspensions and FNAs: Special Handling Characteristics;238
1.7.5.3.4.2.1;DNA/mRNA Collection;238
1.7.5.3.4.2.2;Protein Analysis;238
1.7.5.3.4.2.3;Viable Cell Collection;239
1.7.5.3.5;9.3.5 Operational and Planning Aspects;239
1.7.5.3.6;9.3.6 Examples of Analytical Techniques for PD Endpoints;240
1.7.5.3.6.1;9.3.6.1 DNA Analysis;240
1.7.5.3.6.2;9.3.6.2 Messenger-RNA Analysis;240
1.7.5.3.6.3;9.3.6.3 Protein Analysis: Immunohistochemistry;241
1.7.5.4;9.4 Choosing the Right Tissue for PD Studies: Use of Surrogate Tissues (Nontumor/Normal Tissues) in PD Studies;244
1.7.5.4.1;9.4.1 Skin;244
1.7.5.4.2;9.4.2 Hair;246
1.7.5.4.3;9.4.3 Buccal Mucosa;247
1.7.5.4.4;9.4.4 White Blood Cells and Platelets;249
1.7.5.4.5;9.4.5 Circulating Ligands, Shed Receptors, and Endothelial Cells;251
1.7.5.5;9.5 Choosing the Right Tissue for PD Studies: Circulating Tumor Cells and Tumor Cell-Derived Materials;252
1.7.5.6;9.6 Incorporation of PD Markers Within Early Phase Clinical Trials;254
1.7.5.6.1;9.6.1 Proof of Drug Mechanism;254
1.7.5.6.2;9.6.2 Proof of Concept;257
1.7.5.6.3;9.6.3 Dose/Regimen Selection;259
1.7.5.6.4;9.6.4 Lead/Backup Compound Selection;261
1.7.5.6.5;9.6.5 Surrogate Marker of Clinical Benefit for Regulatory or Individual Patient Decision Making;261
1.7.5.7;9.7 Conclusions;262
1.7.5.8;References;262
1.7.6;Chapter 10: Prediction of Antitumor Response;269
1.7.6.1;10.1 Introduction;269
1.7.6.2;10.2 Tissue Collection Issues;270
1.7.6.3;10.3 Selection of Appropriate Assay;270
1.7.6.4;10.4 Centralized Laboratory;271
1.7.6.5;10.5 Statistical Approaches to Quality Control;272
1.7.6.5.1;10.5.1 Coefficient of Variation;272
1.7.6.5.2;10.5.2 Intraclass Correlation Coefficient and Variance Component Analysis;273
1.7.6.5.3;10.5.3 Case Study;275
1.7.6.6;10.6 Statistical Design of Clinical Trials with a Predictive Marker;275
1.7.6.6.1;10.6.1 Biomarker-Adaptive Threshold Design;276
1.7.6.6.2;10.6.2 Adaptive Signature Design;276
1.7.6.6.3;10.6.3 Power and Sample Size Analysis;277
1.7.6.7;10.7 Analysis and Reporting of Studies with Predictive Markers;279
1.7.6.7.1;10.7.1 Class Prediction;279
1.7.6.7.2;10.7.2 Compound Covariate Method;279
1.7.6.7.3;10.7.3 Weighted Flexible Compound Covariate Method;280
1.7.6.7.4;10.7.4 Random Forest Algorithm and Neural Networks;281
1.7.6.7.5;10.7.5 Leave-One-Out Cross-Validated Class Prediction Model;281
1.7.6.8;10.8 Conclusions;284
1.7.6.9;References;285
1.7.7;Chapter 11: Imaging Studies in Anticancer Drug Development;287
1.7.7.1;11.1 Introduction;287
1.7.7.1.1;11.1.1 Overview of Imaging and Cancer Therapy;287
1.7.7.1.2;11.1.2 Differences Between Imaging and Tissue/Blood Assays;288
1.7.7.1.3;11.1.3 Appropriate Roles;288
1.7.7.1.3.1;11.1.3.1 Early Drug Trials (Phase I/Early Phase II);289
1.7.7.1.3.2;11.1.3.2 Late Phase II/III Drug Trials;289
1.7.7.1.3.3;11.1.3.3 Clinical Drug Therapy;290
1.7.7.2;11.2 Novel Imaging Methods for Drug Development:Overview of Imaging Modalities;290
1.7.7.2.1;11.2.1 Magnetic Resonance Imaging;290
1.7.7.2.2;11.2.2 Magnetic Resonance Spectroscopy;291
1.7.7.2.3;11.2.3 Radionuclide Imaging;292
1.7.7.2.4;11.2.4 Optical Imaging;293
1.7.7.2.5;11.2.5 Ultrasound;293
1.7.7.2.6;11.2.6 Other Imaging;294
1.7.7.3;11.3 Imaging to Define Targets and Select Patientsfor Clinical Trials;294
1.7.7.3.1;11.3.1 Overview;294
1.7.7.3.2;11.3.2 Examples of Imaging Target Expression;295
1.7.7.3.3;11.3.3 Imaging Resistance Factors;298
1.7.7.4;11.4 Imaging to Assess Early Pharmacodynamics/Response;299
1.7.7.4.1;11.4.1 Overview;299
1.7.7.4.2;11.4.2 Examples of Imaging Early Response;299
1.7.7.4.3;11.4.3 Examples of Imaging Pharmacodynamic Effect;302
1.7.7.4.4;11.4.4 Imaging as a Surrogate Endpoint?;302
1.7.7.5;11.5 Analysis and Reporting of Molecular Imaging Data;303
1.7.7.5.1;11.5.1 Standardization;303
1.7.7.5.2;11.5.2 Approach to Imaging Analysis;304
1.7.7.6;11.6 Summary and Conclusions;304
1.7.7.7;References;306
1.8;Part IV;315
1.8.1;Chapter 12: Role of the US Food and Drug Administration in Cancer Drug Development;316
1.8.1.1;12.1 Introduction;316
1.8.1.2;12.2 Role in Premarketing Development;318
1.8.1.2.1;12.2.1 What is an IND Application?;318
1.8.1.2.2;12.2.2 What is Needed for the IND Submission;321
1.8.1.2.2.1;12.2.2.1 Chemistry, Manufacturing, and Control;321
1.8.1.2.2.2;12.2.2.2 Nonclinical Pharmacology/Toxicology;322
1.8.1.2.2.2.1;Toxicology;323
1.8.1.2.2.2.2;Genotoxicity;323
1.8.1.2.2.2.3;Carcinogenicity;323
1.8.1.2.2.2.4;Safety Pharmacology;324
1.8.1.2.2.2.5;Immunogenicity;325
1.8.1.2.3;12.2.3 How to Fulfill IND Requirements;325
1.8.1.2.4;12.2.4 Responsibilities of the IND Holder;325
1.8.1.2.4.1;12.2.4.1 Required Safety Reporting;327
1.8.1.2.4.2;12.2.4.2 Annual Report;327
1.8.1.2.4.3;12.2.4.3 Informed Consent;328
1.8.1.2.4.4;12.2.4.4 Charging to Recover Cost;329
1.8.1.2.4.5;12.2.4.5 Clinical Trial Monitoring (Phase 1, 2 vs. 3);329
1.8.1.2.4.6;12.2.4.6 Data Monitoring Committees;330
1.8.1.2.5;12.2.5 What Are the FDA’s Ongoing Responsibilities?;330
1.8.1.2.6;12.2.6 End of Phase 2 Meetings;331
1.8.1.2.7;12.2.7 Special Protocol Assessments;331
1.8.1.3;12.3 Role in Marketing and Postmarketing;331
1.8.1.3.1;12.3.1 NDA Classification and Content;332
1.8.1.3.2;12.3.2 General Efficacy Requirements;332
1.8.1.3.2.1;12.3.2.1 Efficacy Endpoints for Approval in Oncology;333
1.8.1.3.3;12.3.3 Postmarketing Considerations;334
1.8.1.4;12.4 Other Regulatory Considerations Throughout the Development Cycle;337
1.8.1.4.1;12.4.1 Agency Use of Consultants;337
1.8.1.4.1.1;12.4.1.1 Oncology Drugs Advisory Committee;337
1.8.1.4.2;12.4.2 Diagnostic Tests;338
1.8.1.4.3;12.4.3 Orphan Drug Program;339
1.8.1.4.4;12.4.4 Pediatric Initiatives;340
1.8.1.5;References;341
1.9;Part V;344
1.9.1;Chapter 13: Early Clinical Trials with Cytotoxic Agents;345
1.9.1.1;13.1 Introduction;345
1.9.1.2;13.2 Starting Dose and Schedule of Administration;346
1.9.1.3;13.3 Dose Escalation Methods;347
1.9.1.4;13.4 Correlative Studies in Clinical Trials with Cytotoxic Agents;348
1.9.1.5;13.5 Clinical Trials Combining Cytotoxic Agents;348
1.9.1.5.1;13.5.1 Starting Dose(s);349
1.9.1.5.2;13.5.2 Dose Escalation;349
1.9.1.5.3;13.5.3 DLT Definition;350
1.9.1.5.4;13.5.4 Pharmacokinetics and Drug–Drug Interaction;351
1.9.1.6;13.6 Early Efficacy-Based Trials of Cytotoxic Agents;351
1.9.1.7;13.7 Conclusions;353
1.9.1.8;References;353
1.9.2;Chapter 14: Challenges and Successes in Developing Effective Anti-angiogenic Agents;356
1.9.2.1;14.1 Introduction;356
1.9.2.2;14.2 Angiogenesis and Its Mediators;359
1.9.2.2.1;14.2.1 Angiogenic Growth Factors;362
1.9.2.2.2;14.2.2 The Extracellular Matrix;362
1.9.2.2.3;14.2.3 The Immune System;363
1.9.2.2.4;14.2.4 Endothelial Cells and Endogenous Mediators of Angiogenesis;363
1.9.2.3;14.3 Preclincal Aspects: Assessing Anti-angiogenic Activity and Determining the Starting Dose and Schedule of Administration;364
1.9.2.3.1;14.3.1 Preclinical Screening Assays and Models Assessing Anti-angiogenic Activity;365
1.9.2.3.2;14.3.2 Determining the Starting Dose and Schedule of Administration;368
1.9.2.4;14.4 Clinical Aspects: Dose Escalation and Toxicity;369
1.9.2.4.1;14.4.1 Phase I Clinical Trial Methods and Design;369
1.9.2.4.2;14.4.2 Anti-angiogenic Agents and Toxicity;370
1.9.2.5;14.5 Efficacy-Oriented Anti-angiogenic Single Agent Clinical Trial Design;371
1.9.2.6;14.6 Specific Anti-angiogenic Agents in Clinical Trials;373
1.9.2.6.1;14.6.1 Matrix Metalloproteinase Inhibitors;373
1.9.2.6.2;14.6.2 Non-selective Anti-angiogenic Treatments;374
1.9.2.6.3;14.6.3 Antibody Therapies Against VEGF;374
1.9.2.6.4;14.6.4 Multi-targeted Receptor Tyrosine Kinase Inhibitors;377
1.9.2.6.4.1;14.6.4.1 Sorafenib;379
1.9.2.6.4.2;14.6.4.2 Sunitinib;380
1.9.2.6.4.3;14.6.4.3 Other Anti-angiogenic Multi-targeted Receptor Tyrosine Kinase Agents;381
1.9.2.6.5;14.6.5 Other Approaches to Angiogenesis Inhibition;382
1.9.2.6.5.1;14.6.5.1 Inhibitors of Endogenous Compounds or Receptors;382
1.9.2.6.5.2;14.6.5.2 Small-Molecule Vascular Targeting Agents;383
1.9.2.6.5.3;14.6.5.3 Viral Gene Therapy;384
1.9.2.7;14.7 Combination Therapy with Anti-angiogenics;386
1.9.2.7.1;14.7.1 Anti-angiogenics and Chemotherapy;386
1.9.2.7.2;14.7.2 Anti-angiogenics and Radiation Therapy;387
1.9.2.8;14.8 Correlative Anti-angiogenic Studies;388
1.9.2.8.1;14.8.1 Biologic Markers of Angiogenesis;390
1.9.2.8.2;14.8.2 Radiologic Markers of Angiogenesis;391
1.9.2.8.3;14.8.3 Mechanism-Based Toxicities and Clinical Markers of Anti-angiogenic Effects;392
1.9.2.9;14.9 Conclusion;393
1.9.2.10;References;394
1.9.3;Chapter 15: Targeted Therapeutics in Cancer Treatment;411
1.9.3.1;15.1 Introduction;411
1.9.3.2;15.2 Therapeutic Technologies;412
1.9.3.2.1;15.2.1 Antibodies;412
1.9.3.2.2;15.2.2 Tyrosine Kinase Inhibitors;415
1.9.3.2.3;15.2.3 Nucleic Acids;416
1.9.3.2.3.1;15.2.3.1 RNA Interference;417
1.9.3.2.3.2;15.2.3.2 Nucleic Acid Delivery Systems;417
1.9.3.3;15.3 Cell Cycle;418
1.9.3.4;15.4 Signal Transduction and Protein Kinases;424
1.9.3.4.1;15.4.1 Receptor Kinase Inhibition;425
1.9.3.4.1.1;15.4.1.1 Epidermal Growth Factor Receptor Family;425
1.9.3.4.1.1.1;Anti-EGFR Strategies;426
1.9.3.4.1.2;15.4.1.2 Insulin-Like Growth Factor-I Receptor;429
1.9.3.4.1.3;15.4.1.3 Hepatocyte Growth Factor and c-MET;431
1.9.3.4.1.3.1;HGF/c-MET Pathway Inhibition Strategies;432
1.9.3.4.1.4;15.4.1.4 Determinants of Response to RTK Therapy;434
1.9.3.4.2;15.4.2 Nonreceptor Kinase Inhibition;435
1.9.3.4.2.1;15.4.2.1 PI3Kinase/Akt/Mammalian Target of Rapamycin Pathway;435
1.9.3.4.2.2;15.4.2.2 mTOR-Targeting Agents;436
1.9.3.5;15.5 Mitogen-Activated Protein Kinase Family;439
1.9.3.5.1;15.5.1 Compounds in Development;440
1.9.3.5.1.1;15.5.1.1 RAS Inhibitors;440
1.9.3.5.1.2;15.5.1.2 Raf Inhibitors;442
1.9.3.5.1.3;15.5.1.3 MEK Inhibitors;443
1.9.3.6;15.6 SRC Kinase Inhibitors;445
1.9.3.7;15.7 Apoptosis;446
1.9.3.7.1;15.7.1 Prosurvival Signal Inhibition;447
1.9.3.7.1.1;15.7.1.1 BCL-2;447
1.9.3.7.2;15.7.2 Inhibitor of Apoptosis Protein;449
1.9.3.7.2.1;15.7.2.1 Survivin and XIAP;449
1.9.3.7.2.2;15.7.2.2 Peptidomimetics and Small Molecule Inhibitors of Prosurvival Proteins;450
1.9.3.7.2.3;15.7.2.3 Direct Proapoptosis Activation;451
1.9.3.8;15.8 Challenges in the Clinical Development of STI;452
1.9.3.8.1;15.8.1 Clinical Trials Design Issues;452
1.9.3.8.2;15.8.2 Patient Selection;453
1.9.3.8.3;15.8.3 Study Endpoints;454
1.9.3.8.4;15.8.4 Combination Therapy;455
1.9.3.9;References;456
1.9.4;Chapter 16: Cancer Chemoprevention;470
1.9.4.1;16.1 Introduction;470
1.9.4.2;16.2 Biologic Concepts;471
1.9.4.3;16.3 Population Selection;473
1.9.4.3.1;16.3.1 Cancer Risk Modeling;474
1.9.4.3.2;16.3.2 Convergent Trial Design;475
1.9.4.3.3;16.3.3 Hereditary Cancer Syndromes;476
1.9.4.4;16.4 Selection of Agents;477
1.9.4.4.1;16.4.1 Mechanism-Based Selection of Chemopreventive Agents;478
1.9.4.4.2;16.4.2 Molecular Biomarkers;479
1.9.4.4.3;16.4.3 Combination Strategies;480
1.9.4.4.4;16.4.4 Chemopreventive Agents in Infection-RelatedCancers and Vaccines;480
1.9.4.5;16.5 Endpoint Selection and Optimizing Risk–Benefit;481
1.9.4.5.1;16.5.1 Definitive and Intermediate Endpoints;482
1.9.4.5.2;16.5.2 Optimizing the Risk–Benefit Ratio;483
1.9.4.6;16.6 Conclusions;484
1.9.4.7;References;484
1.9.5;Chapter 17: Combined Modality Therapy in Cancer Management;489
1.9.5.1;17.1 Introduction;489
1.9.5.2;17.2 A Brief Explanation of Radiation Therapy Techniques and Modalities;490
1.9.5.2.1;17.2.1 Radiation Treatment Planning;490
1.9.5.2.2;17.2.2 Biological Basis of Radiation Therapy as It Pertainsto Combined Modality Therapy;492
1.9.5.3;17.3 Rationale for Combined Chemotherapy and Radiation;494
1.9.5.4;17.4 Examples of Combined Modality Success;505
1.9.5.4.1;17.4.1 Head and Neck Cancer;505
1.9.5.4.2;17.4.2 Nonsmall Cell Lung Cancer;508
1.9.5.4.3;17.4.3 Cervical Cancer;510
1.9.5.5;17.5 Esophageal Cancer;512
1.9.5.6;17.6 Conclusions;514
1.9.5.7;References;514
1.9.6;Chapter 18: Cancer Vaccines;524
1.9.6.1;18.1 Introduction;524
1.9.6.2;18.2 Features of the Immune System That Are Required for Successful Cancer Immunotherapy;525
1.9.6.2.1;18.2.1 Tumors Use Multiple Mechanisms To Evade Immune Recognition;525
1.9.6.2.1.1;18.2.1.1 Local Processes;525
1.9.6.2.1.2;18.2.1.2 Systemic Processes;526
1.9.6.3;18.3 Immunotherapy Clinical Trials;528
1.9.6.3.1;18.3.1 Antigen-Based Vaccines;530
1.9.6.3.2;18.3.2 Whole Tumor Cell Vaccines;532
1.9.6.4;18.4 New Immunotherapy Targets;533
1.9.6.4.1;18.4.1 Targeting Immune Checkpoints;534
1.9.6.4.2;18.4.2 Future Expectations;534
1.9.6.5;References;535
1.9.7;Chapter 19: Optimising the Development of Antibodies as Treatment for Cancer;539
1.9.7.1;19.1 Introduction;539
1.9.7.2;19.2 Antibody Structure and Function;539
1.9.7.3;19.3 Mechanisms of Action;540
1.9.7.3.1;19.3.1 Indirect;540
1.9.7.3.1.1;19.3.1.1 Antibody-Dependent Cell Cytotoxicity;540
1.9.7.3.1.2;19.3.1.2 Complement-Dependent Cytotoxicity;541
1.9.7.3.2;19.3.2 Direct;541
1.9.7.3.2.1;19.3.2.1 Cell Surface Receptor Antibodies;541
1.9.7.3.2.2;19.3.2.2 Neutralising Antibodies;541
1.9.7.3.2.3;19.3.2.3 Apoptosis Inducing Antibodies;541
1.9.7.3.2.4;19.3.2.4 Immune Modulation;542
1.9.7.3.2.5;19.3.2.5 Other Strategies;542
1.9.7.4;19.4 Target Validation;542
1.9.7.5;19.5 Antibody Technology: Murine, Chimeric, Humanised, and Fully Human Antibodies;542
1.9.7.6;19.6 Classes of Antibodies;544
1.9.7.6.1;19.6.1 Selected Unconjugated Antibodies Currently in Clinical Use;544
1.9.7.6.1.1;19.6.1.1 Rituximab;544
1.9.7.6.1.2;19.6.1.2 Bevacizumab;544
1.9.7.6.1.3;19.6.1.3 Trastuzumab;545
1.9.7.6.1.4;19.6.1.4 Cetuximab;545
1.9.7.6.1.5;19.6.1.5 Panitumumab;546
1.9.7.6.1.6;19.6.1.6 Alemtuzumab;546
1.9.7.7;19.7 Differences Between Small Molecules and Antibodies;546
1.9.7.8;19.8 Pharmacokinetics of Antibodies;546
1.9.7.9;19.9 Potential Toxicities;548
1.9.7.10;19.10 Preclinical Development: Animal–Human Model Transitions;549
1.9.7.11;19.11 TGN1412: A Cautionary Tale;549
1.9.7.12;19.12 Phase I Trials;551
1.9.7.12.1;19.12.1 Dose Selection;551
1.9.7.12.2;19.12.2 Staggering of Treatment of Patients;552
1.9.7.12.3;19.12.3 Schedule Selection;552
1.9.7.12.4;19.12.4 Selection of Patients;553
1.9.7.12.5;19.12.5 Trial Conduct;553
1.9.7.12.6;19.12.6 Dose Escalation;553
1.9.7.12.7;19.12.7 Pharmacokinetic Sampling;554
1.9.7.12.8;19.12.8 Pharmacodynamic Sampling to Biopsy or Not to Biopsy?;554
1.9.7.12.9;19.12.9 Combinations with Cytotoxic Chemotherapy or Radiotherapy;555
1.9.7.12.10;19.12.10 Combinations with Other Targeted Agents;555
1.9.7.12.11;19.12.11 Optimising Transition from Phase I to Phase II: The “Seamless” Transition;555
1.9.7.13;19.13 Phase II and III Trials;556
1.9.7.13.1;19.13.1 Endpoints and Study Design;556
1.9.7.13.2;19.13.2 Other Endpoint and Design Considerations;557
1.9.7.13.3;19.13.3 Selection of Recommended Phase II Dose;557
1.9.7.13.4;19.13.4 Selection of Patient Population;557
1.9.7.13.5;19.13.5 Moving from the Metastatic to the Adjuvant Setting;558
1.9.7.13.6;19.13.6 Single Agent Versus Combination with Chemotherapy;558
1.9.7.14;19.14 Emerging Technologies: Conjugated Antibodies (Immunoconjugates);559
1.9.7.14.1;19.14.1 Drug-Immunoconjugates;560
1.9.7.14.2;19.14.2 Radio-Immunoconjugates;560
1.9.7.14.3;19.14.3 Immunotoxin Conjugates;561
1.9.7.15;19.15 Other Modulations of Antibody Function;561
1.9.7.15.1;19.15.1 Multivalent Antibodies;561
1.9.7.15.2;19.15.2 Antibody Fragments;562
1.9.7.15.3;19.15.3 Intrabodies;562
1.9.7.15.4;19.15.4 Modulation of Immunogenicity;562
1.9.7.15.4.1;19.15.4.1 Enhanced ADCC;562
1.9.7.15.4.2;19.15.4.2 Modulation of CDC;563
1.9.7.15.4.3;19.15.4.3 Modulation of Other Immune Components;563
1.9.7.16;19.16 Conclusions and Future Directions;564
1.9.7.17;References;564
1.9.8;Chapter 20: Oligonucleotide Therapeutics;572
1.9.8.1;20.1 Introduction;572
1.9.8.2;20.2 Clinical Trials of Oblimersen;574
1.9.8.2.1;20.2.1 Phase III Trial of Oblimersen in Chronic Lymphocytic Leukemia;574
1.9.8.2.2;20.2.2 Bcl-2 Silencing and Chemosensitization;576
1.9.8.2.3;20.2.3 Clinical Trials in Advanced Melanoma;577
1.9.8.2.4;20.2.4 Other Trials of Oblimersen;579
1.9.8.3;20.3 OGX-011;581
1.9.8.4;20.4 AP 12009;582
1.9.8.5;20.5 Affinitak;583
1.9.8.6;20.6 Conclusions;583
1.9.8.7;20.7 RNAi and siRNAs;583
1.9.8.8;References;585
1.9.9;Chapter 21: Anticancer Drug Development in Pediatric Patients;591
1.9.9.1;21.1 Introduction;591
1.9.9.2;21.2 Historical Perspective;591
1.9.9.3;21.3 The Difference Between Children and Adults;593
1.9.9.4;21.4 Drug Development in Pediatrics;595
1.9.9.5;21.5 The Role of Combination Studies;597
1.9.9.6;21.6 Conclusion;600
1.9.9.7;References;600
1.9.10;Chapter 22: Clinical Trials in Special Populations;604
1.9.10.1;22.1 Introduction;604
1.9.10.2;22.2 Organ Dysfunction;604
1.9.10.3;22.3 FDA Regulatory Guidance;606
1.9.10.4;22.4 Pharmacologic Outcomes vs. Toxicity;607
1.9.10.5;22.5 Hepatic Impairment;607
1.9.10.6;22.6 Renal Dysfunction;614
1.9.10.6.1;22.6.1 Measuring Renal Failure;615
1.9.10.7;22.7 Pharmacokinetics and Pharmacodynamics in Organ Dysfunction;617
1.9.10.8;22.8 The Dose Escalation Process;619
1.9.10.9;22.9 Another Challenge: The Elderly;619
1.9.10.10;22.10 The Pediatric Clinical Trial: An Additional Challenge;621
1.9.10.11;22.11 Conclusions;625
1.9.10.12;References;625
1.10;Part VI;630
1.10.1;Chapter 23: NCI-Sponsored Clinical Trials;631
1.10.1.1;23.1 Introduction;631
1.10.1.2;23.2 Agent Discovery and Development;633
1.10.1.2.1;23.2.1 The Drug Development Group;633
1.10.1.2.2;23.2.2 The Developmental Therapeutics Program: Organization and Resources;634
1.10.1.2.3;23.2.3 Programs to Assist Academics and Industry in Preclinical Drug Development Efforts;640
1.10.1.2.3.1;23.2.3.1 Rapid Access to NCI Discovery Resources Program;640
1.10.1.2.3.2;23.2.3.2 Rapid Access to Intervention Development Program;641
1.10.1.2.3.3;23.2.3.3 National Cooperative Drug Discovery Group Program;642
1.10.1.2.3.4;23.2.3.4 International Cooperative Biodiversity Groups Program;642
1.10.1.2.3.5;23.2.3.5 Rapid Access to Preventive Intervention and Development Program;642
1.10.1.3;23.3 Clinical Therapeutics Development and Resources;643
1.10.1.3.1;23.3.1 The Cancer Therapy Evaluation Program: Organization and Structure;644
1.10.1.3.1.1;23.3.1.1 Clinical Grants and Contracts Branch;645
1.10.1.3.1.2;23.3.1.2 Clinical Investigations Branch;646
1.10.1.3.1.3;23.3.1.3 Clinical Trials Monitoring Branch;646
1.10.1.3.1.4;23.3.1.4 Investigational Drug Branch;646
1.10.1.3.1.5;23.3.1.5 Pharmaceutical Management Branch;647
1.10.1.3.1.6;23.3.1.6 Regulatory Affairs Branch;647
1.10.1.3.1.7;23.3.1.7 Protocol and Information Office;647
1.10.1.3.2;23.3.2 CTEP-Sponsored Clinical Development of Investigational Agents and Resources;647
1.10.1.3.2.1;23.3.2.1 Clinical Trials Solicitations and Letters of Intent for Early Clinical Trials;648
1.10.1.3.2.2;23.3.2.2 Protocol Submission and Review;649
1.10.1.3.2.3;23.3.2.3 IND Submission;649
1.10.1.3.2.4;23.3.2.4 Data Reporting;650
1.10.1.3.2.5;23.3.2.5 Safety Data Reporting;650
1.10.1.3.2.6;23.3.2.6 Data and Safety Monitoring;651
1.10.1.3.3;23.3.3 Phase 3 Treatment Trials;652
1.10.1.4;23.4 Conclusion;655
1.10.1.5;References;655
1.11;Index;658
