659M. Hidalgo et al. (eds.), Principles of Anticancer Drug Development, Cancer Drug Discovery and Development, DOI 10.1007/978-1-4419-7358-0, © Springer Science+Business Media, LLC 2011

AAccelerated titration method, 120Adaptive signature design, predictive marker,

263–265, 267–272Adverse events (AE), 129–131, 418, 441,

467, 541, 542Affinity, 39Anti-angiogenic agents

angiogenesis and its mediatorsdegradation and reformation, basement

membrane, 350endogenous inhibitors or receptors,

373–374endothelial cells and endogenous

mediators, 354–355extracellular matrix, 353–354growth factors, 353immune system, 354small-molecule vascular targeting

agents, 374–375viral gene therapy, 375–376

antibody therapies vs. VEGF, 365–368approved agents, 347–348biologic markers

microvascular density (MVD), 381proteomics analysis, 382von Willebrand factor, 381

clinical trial designcytotoxic agents, 363hypoxia inducible factor 1-alpha, 364molecular target expression, 363xenograft models, 362

combination therapychemotherapy, 377–378radiation therapy, 378–379

dose escalationphase I clinical trial methods and

design, 360–361toxicity, 361–362

matrix metalloproteinase inhibitors, 364–365

mechanism-based toxicities and clinical markers

hair depigmentation, 384VEGF-inhibiting therapy, 383

monoclonal antibodies and multi-targeted tyrosine kinase agents, 347, 349

multi-targeted receptor tyrosine kinase inhibitors

other, 372–373vs. preclinical activity, 368–369randomized discontinuation trial

(RDT), 368sorafenib, 370–371sunitinib, 371–372

non-selective anti-angiogenic treatments, 365

preclinical screening assays and modelsadvantages and disadvantages, 357–359Matrigel, 356orthotropic vs. heterotopic implant, 357

starting dose and administration schedule determination, 359–360

surrogate markers, 380tumor regression, 379

Anti-angiogenic mechanisms, 101, 362Antibodies, targeted therapeutics

chimeric, 404monoclonal, FDA approval, 406–407receptor inhibition, 406

Antibody development, cancer treatmentanimal–human model transitions, 545conjugated antibodies

drug-immunoconjugates, 556immunotoxin conjugates, 557radio-immunoconjugates, 556–557

definition, 535direct mechanisms of action

Index

660 Index

Antibody development, cancer treatment (cont.)

apoptosis, 537–538cell surface receptor, 537immune modulation, 538neutralisation, 537other strategies, 538

indirect mechanisms of actioncell cytotoxicity, 536complement-dependent cytotoxicity, 537

other modulationsantibody fragments, 558immunogenicity, 558–560intrabodies, 558multivalent antibodies, 557–558

pharmacokinetics, 542–544phase II and III trials

endpoints and study design, 552metastatic-adjuvant setting, 554other endpoint, 553patient population selection, 553–554selection, recommended phase II

dose, 553single agent vs. chemotherapy

combination, 554–555phase I trials

cytotoxic chemotherapy or radiotherapy, 551

dose escalation, 549–550dose selection, 547–548other targeted agents, 551patient selection, 549pharmacodynamic sampling, 550–551pharmacokinetic sampling, 550schedule selection, 548–549seamless transition, 551–552staggering, patient treatment, 548trial conduct, 549

potential toxicities, 544–545vs. small molecules, 542structure and function, 535–536TGN1412, 545–547types of, 538–539unconjugated antibodies

alemtuzumab, 541bevacizumab, 540–541cetuximab, 541panitumumab, 541rituximab, 540trastuzumab, 541

validation, 538Antibody-directed enzyme prodrug therapy

(ADEPT), 538Antigen-presenting cells (APCs), 520

Antitumour response predictionanalysis and reporting

class prediction, 267compound covariate method (CCM), 267leave-one-out cross-validated class

prediction model, 269–272random forest algorithm and neural

networks, 269weighted flexible compound covariate

method (WFCCM), 268–269assay selection, 258–259centralized laboratory, 259–260statistical approaches to quality control

coefficient of variation (CV), 260–261intraclass correlation coefficient (ICC),

261–263variance component analysis, 261–263

statistical design, predictive markeradaptive signature design, 264–265biomarker-adaptive threshold design, 264power and sample size analysis,

265–266tissue collection issues, 258

Apoptosis proteincaspases, 433inhibitor

direct proapoptosis activation, 443–444peptidomimetics and small molecule, 442survivin and XIAP, 441

prosurvival signal inhibition, 439–441Atomic absorption spectroscopy (AAS),

76–77Atomic spectroscopy

atomic absorption spectroscopy (AAS), 76–77

inductively coupled plasma spectrometry (ICP), 78

BBayesian designs, 152–153BCL-2 proteins

apoptosis-targeted therapy, 439–441lymph node analysis, 441SPC2996, 439

Bioanalytical methodssample preparation

total drug measurements, 67–68unbound drug concentrations, 68–71

sample separationatomic spectroscopy, 76–78gas chromatography, 75–76liquid chromatography, 72–75

small molecule anticancer drugs, 64–66

661Index

validation requirementsaccuracy, 81–83calibration curves, 79–80linearity, 79–80matrix effect in LC-MS/MS based

methods, 85precision, 82range of reliable response, 79–80recovery, 85reproducibility, 83selectivity (specificity), 80sensitivity, 77, 80–81stability, 83–85

Bioavailability, 38, 45Biomarker-adaptive threshold design, 263, 264Biomarkers

anti-angiogenic agentsmicrovascular density (MVD), 381proteomics analysis, 382von Willebrand factor, 381

assay development and validation, 259definition, 215drug development studies, 260enrollment of enriched patient population, 172example, 174indirect method, 173labeled retrospective validation, 172molecular, 472–473, 476PD biomarkers (see Pharmacodynamic

(PD) biomarkers)phase III trials, 171–174prognostic or predictive, 172statistical design, predictive marker

adaptive signature design, 264–265biomarker-adaptive threshold design, 264power and sample size analysis, 265–266

surrogate, 380therapy, 258–259

Biostatisticsaims, endpoints and data analysis, 4–5data description and displays

categorical Variables, 11–12confidence intervals (see Confidence

intervals)continuous variables, 8–11time to event variables, 12–13

farnesyltransferase inhibitor (FTI) tipifarnib, 3–4

hypothesis testingerrors types, 20evidence evaluation through p-values,

17–20from research question to statistical

hypothesis, 17

multivariable regression analysesCox proportional hazards regression,

33–34definition, 30example, 30logistic regression, 31–33

one-and two-sample tests, comparisonchi-square test, 23–25Fisher’s exact test, 25means, 21–23paired data testing, 25–26proportions, 20–21survival times, 26–27

sample size calculationsprecision-based calculations, 27–28test-based calculations, 28–29

variable typescategorical variables, 7continuous variables, 5–6time to event variables, 7transformation, 7–8

Bivariate analysis, 153, 154Blinding. See MaskingBox and whisker plot (boxplot), 9

CCancer chemoprevention

agent selectioncharacteristics, 470combination strategies, 473infection-related cancers and vaccines,

473–474mechanisms, 470molecular biomarkers, 472–473

carcinogenesisgene chip analysis, 465intraepithelial neoplasia (IEN), 464single nucleotide polymorphisms

(SNPs), 464celecoxib, 463definitive and intermediate endpoint

selection, 474finasteride, 463population selection

cancer risk modeling, 467–468convergent trial design, 468–469hereditary cancer syndromes,

469–470premalignant-malignant cells

transition, 466risk-benefit ratio optimization

COX-2 inhibitor, 476UGT1A1*28 polymorphism, 477

662 Index

Cancer therapy evaluation program (CTEP)investigational agents and resources

clinical trials solicitations and letters, 648–649

data and safety monitoring, 651–652data reporting, 650IND submission, 649protocol submission and review, 649safety data reporting, 650

organization and structureclinical grants and contracts branch

(CGCB), 645–646clinical investigations branch (CIB), 646clinical trials monitoring branch

(CTMB), 646investigational drug branch (IDB), 646organization and mission, 645pharmaceutical management branch

(PMB), 647protocol and information office’s

(PIO), 647regulatory affairs branch (RAB), 647

phase 3 treatment trials, 652–655Cancer vaccines

immunotherapy clinical trialsactive, 524antigen-based vaccines, 525–527passive, 523vascular endothelial growth factor-A

(VEGF-A), 523VEGF–EGFR pathway inhibition, 524whole tumor cell vaccines, 527–528

immunotherapy targetsimmune checkpoints, 529immunologic recognition and

eradication, 530viral particles and bacterial delivery

systems, 528mechanisms, tumor immune evasion

local processes, 520–521systemic processes, 521–523T-cell activation vs. suppression,

520, 522tumor antigen recognition vs. tumor

escape, 519Categorical Variables, 7Cervical cancer, chemoradiation

acute toxicity, 505vs. radiation therapy, survival rates, 495, 504RTOG 0417, 506

Chemoprevention agentscharacteristics, 470combination strategies, 473infection-related cancers and vaccines

immunization strategy, 474neoplastic development, 473

mechanismscelecoxib-related cardiovascular

adverse events, 472COX-2 inhibitors, 471

molecular biomarkerscyclin D1 genotype, 472rapamycin inhibition, 473safety and effectiveness, 472

Chemoradiation, combined modality therapycervical cancer

acute toxicity, 505vs. radiation therapy, survival rates,

495, 504RTOG 0417, 506

head and neck cancerepidermal growth factor receptor

(EGFR) expression, 501locoregional control and organ

preservation, 500overall survival rates, vs. radiation

alone, 493, 499primary endpoint, local-regional

control, 499nonsmall cell lung cancer (NSCLC)

CALGB 8433, 502median progression-free and overall

survival rates, 503RTOG 0324, 504sequential vs. concurrent chemotherapy,

494, 503Chemotherapy agents, 592Chemotherapy-anti-angiogenics

metronomic approaches, 378normalization window, 377

Chi-square test, 23–25Chronic kidney disease (CKD), 605Clearance (CL), 38, 51–52, 191Clinical drug therapy, 278Clinical pharmacology

definition, 37goal, PK study, 43–44modelling terms, 39–40number of patients, 42–43pharmacodynamic (PD) terms, 39pharmacokinetics (PK)

definition, 44drug distribution, 45drug elimination, 47–49drug metabolism, 45–47models, 49–61 (see also

Pharmacokinetics)non-compartmental type, 55–56

663Index

non-linear type, 54physiologically-based pharmacokinetic

(PBPK) models, 56–59population pharmacokinetics, 60–61rate of drug absorption, 44

pharmacokinetic (PK) terms, 38sampling intensity, 42–43sampling schedule and study design, 40–42

Clinical trials, oblimersenadvanced melanoma

dacarbazine, 574neutropenia and thrombocytopenia, 576proliferation vs. vascularization,

rate of, 575Bcl-2 silencing and chemosensitization, 573chronic lymphocytic leukemia

demographic characteristics, 572responsive vs. refractory, 571

othersBcl-2 protein, 576dexamethasone, 578gymnotic delivery, 577response rates, 576

Clinical trials, special populationscancer clinical trials, elderly populations,

620–622dose escalation process, 618FDA regulatory guidance

abnormal liver dysfunction, 606hepatic dysfunction, 605

hepatic impairmentChild-Pugh classification, 608indices, 607–608international normalized ratio (INR)

via coagulation activation, 609liver disease, causes of, 606–607Mayo end-stage liver disease (MELD)

score, 608NCI stratifications, 609renal and hepatic dysfunction, 609–612

neutropenic infection prevention, 619organ dysfunction

chemotherapeutic agents, 603hepatic infiltration, 604pharmacokinetics and

pharmacodynamics, 616–617pediatric

factors, 623recommended phase II dose, 620rolling six design, 623

pharmacologic outcomes vs. toxicity, 606renal dysfunction

creatinine clearance estimation, 614cystatin C, 616

drug elimination, 614extracellular fluid volume, 615methods, 614phase II metabolic reactions, 613

survival rates, 618Clonogenic assays, 101Coefficient of variation (CV), 191, 260–262Combined modality therapy (CMT)

chemoradiationcervical cancer, 504–506head and neck cancer, 499–502nonsmall cell lung cancer (NSCLC),

502–504esophageal cancer

disease control and survival, 507locoregional relapse, 506median survival rates, concurrent

chemoradiation, 496, 506radiation therapy vs. chemoradiation, 507

radiation therapy techniques and modalitiesbiological basis, 486–488radiation treatment planning, 484–486

radiotherapy delivery, 483rationale, chemotherapy-radiation

capecitabine, 498cervical cancer, survival rates, 488, 495cisplatin, 497esophageal cancer, median survival

rates, 488, 4965-flourouracil, 497head and neck cancer, overall survival

rates, 488, 493phase III clinical trials, gastrointestinal

tumors and glioblastoma, 488–492sequential vs. concurrent

chemoradiation, 488, 494systemic therapies, 488temozolomide, 498in vitro methods, 488

Compartmental modelling, 39Compound covariate method (CCM), 267Computer Assisted Drug Design, 98Confidence intervals

for means and differences in means, 14–15

for proportions and comparisons of proportions, 15–16

for time-to-event parameters, 16width, 14

CONSORT Statement, 185Continual reassessment method (CRM), 120Continuous variables, 5–6Cox proportional hazards regression, 33–34CTEP. See Cancer therapy evaluation program

664 Index

Cytotoxic agents, early clinical trialsadministration schedules, 336–337correlative studies, 338DLT definition, 340–341dose escalation, 337, 339–340efficacy-based trials

active/inactive drug, 343growth modulation index, 342response criteria in solid tumors

(RECIST), 341vs. noncytotoxic agents, 336pharmacokinetics and drug-drug

interaction, 341starting dose, 336–337, 339

DData analysis and reporting

measurements for proportionsnumber needed to be treated, 180Odds ratio, 180–181relative risk reduction, 180risk and relative risk, 180

measurements for time to event outcomes, 181

subgroup analyses, 182–183univariable and multivariable testing,

181–182Data Safety Monitoring Board (DSMB). See

Independent Data Safety Monitoring Committee

Death effector domain (DED), 433Decision theoretic designs, 153Developmental therapeutics program (DTP)

activities, 635COMPARE, 637drug discovery and preclinical testing,

634–635drug screening schema, 636–637organization and mission, 636

Disease progression, 144, 154Dose-dependent pharmacokinetics. See

Nonlinear pharmacokineticsDose-limiting toxicity, 337Dose-limiting toxicity (DLT), 117–119,

121, 321Dose–response relationship, 37Dotplot, 9–11Drug absorption, 44, 45Drug distribution, 45, 46, 199Drug dose, 37Drug elimination, 47–48Drug exposure, 37Drug-induced liver injury (DILI), 605

Drug interval/holiday, 336Drug metabolism, 45–48, 197, 208Drug scheduling and administration

sequencing, 195–196DTP. See Developmental therapeutics

program

EEarly drug trials (phase I/early phase II), 277Efficacy, 39, 102–103Efficacy models, 102Elimination half-life, 38, 40Elimination rate constant, 38, 50Empirical vs. rational discovery and

development strategies, 93–95End of phase 2 (EOP2) meetings, 320Endogenous inhibitors or receptors

ABT-510, 373PI-88 activity, 374

End-stage renal disease (ESRD), 605Epidermal growth factor receptor

(EGFR), 537Equilibrium dialysis, 69Equivalence studies, 171European medicines agency (EMEA), 590

FFactorial designs, 169–170, 321Farnesyltransferase inhibitor (FTI) tipifarnib,

3–4Fisher’s exact test, 25Fixed dose escalation, 118Food and drug administration modernization

act, 590

GGas chromatography (GC), 75–76Glomerular filtration rate (GFR), 614

HHead and neck cancer, chemoradiation

epidermal growth factor receptor (EGFR) expression, 501

locoregional control and organ preservation, 500

overall survival rates, vs. radiation alone, 493, 499

primary endpoint, local-regional control, 499HED calculation. See Human equivalent dose

(HED) calculation

665Index

Hepatic impairment, clinical trialsChild-Pugh classification, 608indices, 607–608international normalized ratio (INR) via

coagulation activation, 609liver disease, causes of, 606–607Mayo end-stage liver disease (MELD)

score, 608NCI stratifications, 609renal and hepatic dysfunction, 609–612

Histogram, 9–11Human equivalent dose (HED) calculation,

124–128, 547Hypothesis testing

errors types, 20evidence evaluation through p-values,

17–20from research question to statistical

hypothesis, 17

IImage-guided radiation therapy (IGRT), 485Imaging studies

early pharmacodynamics/response assessment

examples, 287–290overview, 287surrogate endpoints, 290–291

imaging vs. tissue/blood assays, 276modalities

magnetic resonance (MR), 278–279magnetic resonance spectroscopy

(MRS), 279–280optical, 281others, 282radionuclide, 280–281ultrasound, 281

molecular imaging data analysis and reportingapproaches, 292standardization, 291–292

overview, 275–276roles

clinical drug therapy, 278early drug trials (phase I/early phase

II), 277late phase II/III drug trials, 277–278

therapeutic targetsexpression, 283–285overview, 282–283resistance factors, 286–287

Immunogenicity modulationscomplement-dependent cytotoxicity

(CDC), 559

enhanced antibody-dependent cell cytotoxicity (ADCC), 558–559

other immune components, 559–560Immunotherapy clinical trials, cancer

vaccinesactive, 524antigen-based vaccines

CEA, 526heat shock proteins (HSP), 525mucin-1, 526mutated k-ras vaccines, 525

passive, 523VEGF–EGFR pathway inhibition, 524whole tumor cell vaccines

granulocyte/macrophage colony-stimulating factor (GM-CSF), 527

serial analysis of gene expression (SAGE), 528

IND. See Investigational new drugIndependent Data Safety Monitoring

Committee, 178Inductively coupled plasma spectrometry

(ICP), 78In silico screening, 98Intensity-modulated radiation therapy

(IMRT), 485Intent to treat (ITT) analysis, 179International Cooperative Biodiversity Group

(ICBG) program, 642Interquartile range (IQR), 9Intraclass correlation coefficient (ICC),

260–263Intrinsic activity, 39Investigational new drug (IND)

application, 307–310requirements fulfillment, 314responsibilities of its holder

annual report, 316charging to recover cost, 318clinical trial monitoring, 318–319Data Monitoring Committees

(DMCs), 319Informed Consent, 317–318safety reporting, 316

submissionchemistry, manufacturing and control,

310–311nonclinical pharmacology/toxicology,

311–314In vitro pure chemical screens, 98

KKaplan–Meier curve, 12–13

666 Index

LLarge volume screening methods

ancillary needs, 97–98historical perspective, 95–96positive and negative results management,

100–102types, 98–100

Late phase II/III drug trials, 277–278Leave-one-out cross-validated class prediction

model, 269–272Linear pharmacokinetics, 39Liquid chromatography

electrical conductivity, 74fluorescence, 74mass spectrometry (MS), 74–75ultraviolet and visible spectroscopy

(UV/VIS), 73Liquid-liquid extraction, 67, 68Logistic regression, 31–33

MMagnetic resonance (MR) imaging,

278–279Magnetic resonance spectroscopy (MRS),

279–280Marketing and postmarketing role, US FDA

considerations, 323–326general efficacy requirements, 321–323NDA classification and content, 321

Masking, 30, 168–169Maximal tolerated dose (MTD), 337, 339–340,

593, 639Maximum concentration, 38Maximum response, 39Medical Dictionary for Regulatory Activities

(MedDRA), 129, 131MEK inhibitors

CI-1040, 431molecular determinants, 432pharmacodynamic analysis, 431three-dimensional structures, 430

Microdialysis, 70–71“3 + 3” Modified dose escalation Fibonacci

design, 118–121, 618Molecular and chemical descriptors

bioengineering, 93cancer therapeutic types, 90–93natural products, 92synthetic structures, 92

MTD confirmation phase, 118Multiple randomizations, 165–166Multi-stage phase II design, 148

Multi-targeted receptor tyrosine kinase inhibitors

other, 372–373vs. preclinical activity, 368–369randomized discontinuation trial

(RDT), 368sorafenib, 370–371sunitinib, 371–372

Multivariable regression analysesCox proportional hazards regression,

33–34definition, 30example, 30logistic regression, 31–33

Mutational activation, 94

NNational Cancer Center Network

(NCCN), 619National Cancer Institute (NCI)-sponsored

clinical trialscomponents, 643CTEP

investigational agents and resources, 647–652

organization and structure, 644–647phase 3 treatment trials, 652–655

DCTD organization and mission, 632drug development group (DDG)

early and late screening, 634preclinical and clinical development

program, 638DTP

activities, 635COMPARE, 637drug discovery and preclinical testing,

634–635drug screening schema, 636–637organization and mission, 636

NCI experimental therapeutics program (NExT), 633

pharmaceutical resources branch (PRB), activities, 639

programs, preclinical drug developmentInternational Cooperative Biodiversity

Group (ICBG), 642National Cooperative Drug Discovery

Group (NCDDG), 642Rapid Access to Intervention

Development (RAID), 641–642Rapid Access to NCI Discovery

Resources (RAND), 640–641

667Index

Rapid Access to Preventive Intervention and Development (RAPID), 642–643

toxicology and pharmacology branch (TPB), activities, 639

types of, 631National Cooperative Drug Discovery Group

(NCDDG) program, 642Natural killer (NK) cells, 520NCI 60, 97, 99–100Neural networks, 97, 269New approaches to neuroblastoma therapy

(NANT), 593NOAEL determination. See No observed

adverse effect level determinationNoncompartmental modelling, 39Non-compartmental pharmacokinetics,

55–56Non-eukaryotic cell models, 100Non-inferiority studies, 171Nonlinear pharmacokinetics, 39Nonreceptor kinase inhibition

mTOR-targeting agentsclinical antitumor activity, 425–426downstream effects, 426rapamycin, 423toxicities, 424

rapamycin pathwaycellular translation machinery, 423phosphatase and tensin homolog, 422raptor, 423

Nonsmall cell lung cancer (NSCLC), chemoradiation

CALGB 8433, 502median progression-free and overall

survival rates, 503RTOG 0324, 504sequential vs. concurrent chemotherapy,

494, 503No observed adverse effect level (NOAEL)

determination, 123–127, 546, 547Nucleic acids, targeted therapeutics

antisense oligonucleotide design, 408delivery systems, 409–410RNA interference, 409

OObjective response rate, 142–143, 154Oblimersen, clinical trials

advanced melanomadacarbazine, 574neutropenia and thrombocytopenia, 576

proliferation vs. vascularization, rate of, 575

Bcl-2 silencing and chemosensitization, 573chronic lymphocytic leukemia

demographic characteristics, 572responsive vs. refractory, 571

othersBcl-2 protein, 576dexamethasone, 578gymnotic delivery, 577response rates, 576

Odds ratio, 32, 180Oligonucleotide therapeutics

affinitak, 580AP 12009, 579clinical trials, oblimersen

advanced melanoma, 574–576Bcl-2 silencing and chemosensitization,

573chronic lymphocytic leukemia,

571–573others, 576–578

heparin-binding proteins, 570immunostimulatory properties, 570OGX-011

docetaxel vs. docetaxel, 579pro-apoptotic bax protein, 578

pseudocatalytic mechanism, 570RNAi and siRNAs, 580–582

Oncology drug development, 190–193Oncology Drugs Advisory Committee

(ODAC), 326–327Optical imaging, 281Organ dysfunction, clinical trials

chemotherapeutic agents, 603hepatic infiltration, 604pharmacokinetics and pharmacodynamics

14C-labeled carbon dioxide, 617therapeutic index, 616

Orphan Drug program, 328–329

PPaired data testing, 25–26PD biomarkers. See Pharmacodynamic (PD)

biomarkersPediatric brain tumor consortium

(PBTC), 593Pediatric Initiatives, 329–330Pediatric investigational plan (PIP), 590Pediatric patients

adult oncology population, 589children vs. adults

668 Index

Pediatric patients (cont.)acute lymphoblastic leukemia

(ALL), 592age-dependence, 591antineoplastic agent, 592drug delivery mechanism, 591

drug developmentdose-limiting toxicity (DLT), 593insulin-like growth factor 1 receptor

(IGF-1R), 595maximally tolerated dose (MTD), 593pharmacokinetic profile, 594preclinical testing, 595

drug testing, 590minimal risk, definition, 590role of, combination

anticancer therapy, 595chemotherapy delivery, 597clofarabine, 596drugability, 598irinotecan, 597topotecan, 596

Pediatric pharmacology research unit (PPRU) network

Pediatric preclinical testing program (PPTP), 595

Pediatric tumors, 592Pharmacodynamic (PD) biomarkers

circulating tumor cells and tumor cell-derived materials, 240–242

incorporation of PD markersdose/regimen selection, 247–248lead/back-up compound selection, 249proof of concept, 245–247proof of drug mechanism, 242–245surrogate marker of clinical benefit,

249–250rapamycin, tumor biopsies, 229–231role in oncology and drug development,

215–217specific drug, 217–219surrogate tissues

buccal mucosa, 235–237hair, 234–235normal tissue vs. solid tumor tissues,

232–234skin, 229–230white blood cells and platelets,

237–239tumor-derived tissue and methodologies

analytical techniques for PD endpoints, 228–231

anatomical sites to be biopsied, 222–223

operational and planning aspects, 227processing and preservation, 224–227tissue acquisition methods, 220–222tissue heterogeneity, 223–224

Pharmacodynamics (PD), 37, 229–231, 287–291, 616–617

Pharmacokinetic-pharmacodynamic relationships

clinical developmentdose-escalation schemes, 194parameter estimates, 195starting dose selection, 193–194

preclinical development, 193Pharmacokinetics (PK)

commonly used terms, 44compartmental modelling

multi-compartment model, 52–54one-compartment model, 50–52

definition, 37, 44drug distribution, 45drug elimination, 47–49drug metabolism, 45–47goal, 43linear, 39non-compartmental type, 55–56non-linear type, 39, 54physiologically-based pharmacokinetic

(PBPK) models, 56–59population pharmacokinetics, 60–61rate of drug absorption, 44

Pharmacokinetic studies, early anticancer drug development

dose adaptationfeedback controlled-dosing, 209–210therapeutic drug monitoring, 209

oncology drug development, 190–193pharmacokinetic–pharmacodynamic

relationshipsclinical development, 193–195preclinical development, 193

pharmacokinetic variability sourcesage, 197–200body size and body composition,

196–197drug interactions, 204–207drug scheduling and administration

sequencing, 195–196inherited genetic factors, 208–209pathophysiological changes,

200–203sex dependence, 203

Pharmacokinetic variability sourcesage

absorption changes, 197–198

669Index

changes in hepatic metabolism, 199–200

changes in renal function, 199volume of distribution changes,

198–199body size and body composition, 196–197drug interactions

complementary and alternative medicine co-administration, 206–207

non-chemotherapeutic drugs co-administration, 204–206

drug scheduling and administration sequencing, 195–196

inherited genetic factors, 208–209pathophysiological changes

disease effects, 200hepatic impairment effects, 201–202renal impairment effects, 200–201serum proteins effects, 203

sex dependencechemotherapeutic drugs

co-administration, 204Pharmacology models, 102Phase I clinical trials

design options and dose escalationaccelerated titration method, 120continual reassessment method

(CRM), 120“fixed dose” escalation, 118–121“3 + 3” modified Fibonacci design,

118–121rolling six design, 120–121

ethical considerationsrisk-benefit ratio, 135–137therapeutic intent, 134–135

goal, 117informed consent, 136–137phase I evaluation and end-points

correlative studies, 132–133optimal biologic dose for novel,

non-toxic agents, 133–134radiographic evaluation, 132reporting of toxicities, 129–131

starting doses and schedules selectionmodern method, 124–128other methods, 128preclinical pharmacology studies,

121–122preclinical toxicology studies, 122traditional method, 123–124

Phase I evaluation and end-pointscorrelative studies, 132–133objectives, 128

optimal biologic dose for novel, non-toxic agents, 133–134

radiographic evaluation, 132reporting of toxicities

adverse events (AE), 129–130serious adverse events (SAE), 130–131

Phase III clinical trialsbiomarkers

enrollment of enriched patient population, 172

example, 174indirect method, 173labeled retrospective validation, 172prognostic or predictive, 172

data analysis and reportingmeasures of effectiveness, 179–181subgroup analyses, 182–183univariable and multivariable testing,

181–182endpoints

measurement criteria, 166–167primary vs. secondary, 166surrogate or substitute, 167–168

equivalence and non-inferiority design, 171

factorial designs, 169–170Independent Data Safety Monitoring

Committee, 178masking, 168–169multiple arm studies, 169phase II/III design, 177–178population, 164–165randomization

multiple, 165–166stratification, 166

statistical considerationshypothesis testing and confidence

intervals, 174–175interim analyses, 176–177sample size, 175–176

termination of study, 178–179transparency and consistency

CONSORT Statement, 185trial registries, 183–184

Phase II trialschallenges, 154–155elements, 155endpoints

disease progression, 144objective response rate, 142–143others, 145toxicity, 143–144

factors influencing design, 142hypothesis-testing framework, 155–157

670 Index

Phase II trials (cont.)multi-stage, 148single stage, 145–146two-stage, 146–148

randomized trialconcurrent “comparator” arm, 148–149discontinuation trials, 150–151experimental arms, 149–150phase II/III trials, 151screening trials, 150

sample sizes, 155, 158theoretical frameworks

Bayesian designs, 152–153bivariate analysis, 153decision theoretic designs, 153

Physiologically-based pharmacokinetic (PBPK) models, 56–59

Physiologically based pharmacokinetics (PBPK), 39–40

Platelet-derived growth factor receptor (PDGFR), 537

Population pharmacokinetic modelling, 39Population pharmacokinetics, 60–61Population selection, cancer chemoprevention

cancer risk modelingcyclin D1 genotypes, 467estimated event rate, 468Gail model, 497

convergent trial designangiogenic switch, 468early-phase trial designs, 469

hereditary cancer syndromescelecoxib vs. placebo, 470familial adeomatous polyposis

(FAP), 469nonsteroidal anti-inflammatory

agent, 470premalignant-malignant cells transition, 466

Potency, 39Precision-based sample size calculations,

27–28Preclinical models

cancer drug development, in vivo models, 96COMPARE algorithm, 97empirical drug discovery, 89, 91empirical vs. rational discovery and

development strategies, 93–95large volume screening methods

ancillary needs, 97–98historical perspective, 95–96positive and negative results

management, 100–102types, 98–100

molecular and chemical descriptorsbioengineering, 93cancer therapeutic types, 90–93natural products, 92synthetic structures, 92

targeted cancer drug discovery, 89, 90in vivo evaluation

clinical correlation, in vivo screening and model results, 107–109

mouse models, 103–107overview, 102–103styles of, 104

Preclinical screening assays and models, anti-angiogenic activity

advantages and disadvantages, 357–359Matrigel, 356orthotropic vs. heterotopic implant, 357

Premarketing development role, US FDAend of phase 2 (EOP2) meetings, 320IND application, 307–310IND holder responsibilities, 314–319IND requirements fulfillment, 314IND submission, 310–314ongoing responsibilities, 319–320special protocol assessments (SPA), 320

Prognostic (predictive) biomarker, 172, 225Progression based endpoints. See Disease

progressionProgression free rate (PFR), 342Protein precipitation, 67, 68, 70p-values, 17–20

RRadiation therapy-anti-angiogenics

sequencing and timing, 378toxicity, 379

Radiation therapy techniques and modalitiesbiological basis

diffusion-limited hypoxiaDNA damageionizing radiationoxygenated vs. hypoxic settingrepopulation

radiation treatment planningdose clouds, 485–486dose painting, 485image-guided radiation therapy

(IGRT), 486intensity-modulated radiation therapy

(IMRT), 485simulation technologies, 494

Radionuclide imaging, 280–281

671Index

Raf inhibitorssorafenib, 429VEGF signal transduction, 430

Random forest algorithm, 269Randomization

multiple, 165–166stratification, 166

Randomized phase II trialsconcurrent “comparator” arm, 148–149discontinuation trials, 150–151experimental arms, 149–150phase II/III trials, 151screening trials, 150

Rapid Access to Intervention Development (RAID) program, 641–642

Rapid Access to NCI Discovery Resources (RAND) program, 640–641

Rapid Access to Preventive Intervention and Development (RAPID) program, 642–643

Rational drug development strategies, 94Receptor kinase inhibition

epidermal growth factor receptor (EGFR)cetuximab, 415gefitinib, 415intracellular signals, 413lapatinib, 416monoclonal antibodies, 414single-agent trastuzumab, 415

hepatocyte growth factor (HGF) and c-MET

ARQ197, 419MP470, 421PF-02341066, 420

insulin-like growth factor-I receptor (IGF-1R), 416–418

molecular determinantsintracellular signal transduction

pathways, 422sensitivity, anitibodies, 421

Relative sensitivity, 77Renal dysfunction, clinical trials

creatinine clearance estimation, 614cystatin C, 616drug elimination, 614extracellular fluid volume, 615methods, 614phase II metabolic reactions, 613

Repeatability and reproducibility (R&R) study, 260

Response, 31, 37, 39Response criteria in solid tumors

(RECIST), 341

Response Evaluation Criteria in Solid Tumors (RECIST), 132, 142–143, 154, 291, 341, 342, 370, 379

Rolling six design, 120–121, 594, 623

SSample preparation, bioanalytical methods

total drug measurementsliquid-liquid extraction, 68protein precipitation, 67, 70solid phase extraction, 67–68

unbound drug concentrationsequilibrium dialysis, 69microdialysis, 70–71protein precipitation, 67, 70ultracentrifugation, 69ultrafiltration, 69

Sample separation, bioanalytical methodsatomic spectroscopy

atomic absorption spectroscopy (AAS), 76–77

inductively coupled plasma spectrometry (ICP), 78

gas chromatography (GC), 75–76liquid chromatography

electrical conductivity, 74fluorescence, 74mass spectrometry (MS), 74–75ultraviolet and visible spectroscopy

(UV/VIS), 73Serious adverse events (SAE), 130–131, 541,

542, 579Short-term/prolonged daily administrations, 336Single stage phase II trials, 145–146Small-molecule vascular targeting agents

auristatin, 374combretastatin A-4 phosphate, 375

Solid phase extraction, 67–68Special protocol assessments (SPA), 320Starting doses and schedules selection

modern methodanimal doses to human equivalent

doses conversion, 125, 128human equivalent dose (HED)

calculation, 124–128most appropriate species selection, 124,

126, 127no observed adverse effect level

(NOAEL) determination, 123–127safety factor, 127–128

other methods, 128preclinical pharmacology studies, 121–122

672 Index

Starting doses and schedules selection (cont.)preclinical toxicology studies, 122traditional method, 123–124

Stereotactic body radiation therapy (SBRT), 483STI, targeted therapeutics

clinical trials designmaximum-tolerated dose, 444pharmacodynamic response, 445

combination therapyEGFR inhibitors, 447vascular endothelial cell growth factor

receptor, 448endpoints

efficacy evaluation, 446imaging techniques, 447

patient selection, 445–446Stratification, 166Surrogate markers, 249–250, 338, 379Survival times, 26–27

TTargeted therapeutics

antibodieschimeric, 404monoclonal, FDA approval, 406–407receptor inhibition, 406

apoptosis proteincaspases, 433inhibitor, 441–443prosurvival signal inhibition, 434–441

cell cycleBI-2536, 410cyclin-dependent kinase inhibitors,

407–408flavopiridol, 407mitosis-specific inhibitors, 408–409ON01910, 410pharmacologic CDK inhibitors

(CDKI), 407phases, 410PLK-1 protein instability, 411

clinical development, STIclinical trials design, 444–445combination therapy, 447–448endpoints, 446–447patient selection, 445–446

intracellular targets and compound, 404–405

mitogen-activated protein kinaseconformational changes, 427MEK inhibitors, 430–432Raf inhibitors, 429–430RAS inhibitors, 427–428

nucleic acidsantisense oligonucleotide design, 408delivery systems, 409–410RNA interference, 409

signal transduction and protein kinasesbortezomib inhibition, 412extracellular ligand-binding domain, 411nonreceptor kinase inhibition, 422–426receptor kinase inhibition, 412–422

small molecule inhibitors, 403SRC kinase inhibitors

AZM475271, 433dasatinib, 432

tyrosine kinase inhibitorschimeric LNA–DNA molecules, 408DFG, 407structure, 408

Test-based sample size calculations, 28–29Time to event variables, 7Time to maximum concentration, 38Tissue acquisition methods

core biopsies, 220–221fine needle aspirate (FNA) biopsy,

220–222third-space collections (ascites, pleural

fluid), 222Tissue management and preservation

cell suspensions and FNAs: special handling characteristics

DNA/mRNA collection, 226protein analysis, 226viable cell collection, 227

surgical and core biopsies processingfrozen tissues, 225paraffin-embedded tissues for IHC,

225–226Toxicity, 43, 117, 122, 129, 143–144, 311Tumor-derived tissue and methodologies, PD

studiesanalytical techniques for PD endpoints

DNA analysis, 228messenger RNA analysis, 228protein analysis, 229–231

anatomical sites to be biopsied, 222–223

cell suspensions and FNAsDNA/mRNA collection, 226protein analysis, 226viable cell collection, 227

operational and planning aspects, 227surgical and core biopsies processing

frozen tissues, 225paraffin-embedded tissues for IHC,

225–226

673Index

tissue acquisition methodscore biopsies, 220–221fine needle aspirate (FNA) biopsy,

220–222third-space collections (ascites, pleural

fluid), 222tissue heterogeneity, 223–224

Two-stage phase II trials, 146–148Tyrosine kinase inhibitors, targeted

therapeuticschimeric LNA–DNA molecules, 408DFG, 407structure, 408

UUltracentrifugation, 69Ultrafiltration, 69Ultrasound imaging, 281Unbound drug concentrations

equilibrium dialysis, 69microdialysis, 70–71protein precipitation, 67, 70ultracentrifugation, 69ultrafiltration, 69

US Food and Drug Administration (FDA)marketing and postmarketing role

considerations, 323–326general efficacy requirements, 321–323NDA classification and content, 321

premarketing development roleend of phase 2 (EOP2) meetings, 320IND application, 307–310IND holder responsibilities, 314–319IND requirements fulfillment, 314IND submission, 310–314ongoing responsibilities, 319–320special protocol assessments (SPA), 320

regulatory considerationsagency use of consultants, 326–327diagnostic tests, 327–328Orphan Drug program, 328–329Pediatric Initiatives, 329–330

VVariance component analysis, 260–263Vascular endothelial growth factor-A

(VEGF-A), 523Vascular endothelial growth factor receptor

(VEGFR), 537Viral gene therapy

adenovirus dl922/947, 375viable tumor rim, 376

Volume of distribution, 38, 45, 51, 198–199

WWeighted flexible compound covariate method

(WFCCM), 268–271