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Non-Clinical Drug Development

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Title: Non-Clinical Drug Development


1
Non-Clinical Drug Development
  • Chris H. Takimoto, MD, PhD
  • Institute for Drug Development
  • San Antonio Cancer Institute
  • University of Texas Health Science Center
  • San Antonio, TX

2
Drug Development
  • Drug discovery screening
  • Non-clinical development
  • Animal scale up
  • Phase I studies
  • Phase II studies
  • Phase III studies

Specific examples from anticancer drug development
3
Overview of Anticancer Drug Development
NDA
IND
Chemical Synthesis and Formulation Development
Animal Models for Efficacy
Assay Development
Dose Escalation and Initial PK
Proof of Concept and Dose Finding
Large Efficacy Trials with PK Screen
Animal PK and PD
PK/PD Studies in Special Populations
PHASE I
PHASE II
PHASE III
Pre-Clinical Development
Clinical Development
4
Goals of Non-Clinical Testing of Small Molecule
Drugs and Biologicals
  • To characterize potential adverse drug effects
  • Define end organ toxicities
  • Define reversibility of toxicity
  • To characterize pharmacokinetic profile
  • To characterize beneficial pharmacodynamic
    effects
  • Proof of principle
  • To guide safe use in human clinical studies
  • To determine a safe reasonable starting dose
  • Provide monitoring guidelines for the clinical
    study
  • Provide sufficient data to conclude that patients
    are not exposed to unreasonable risks
  • Potential for benefit must also exist

5
Oncology drug development is changing in the new
era of targeted cancer therapies
6
Conventional Wisdom in the New Age of Modern Drug
Development
  • Targeted therapies are unique and distinct from
    classic cytotoxic chemotherapies
  • Classical chemotherapy poisons
  • All new agents entering the clinical have well
    defined molecular targets
  • Conventional clinical study designs are outdated,
    outmoded, and poorly-suited to develop targeted
    therapies
  • Biomarkers rule!

7
What are Targeted Therapies?The NCIs Definition
  • From the NCIs internet fact sheet
  • Targeted cancer therapies use drugs that block
    the growth and spread of cancer.
  • They interfere with specific molecules involved
    in carcinogenesis and tumor growth.
  • Because scientists call these molecules
    molecular targets, these therapies are
    sometimes called molecularly-targeted
    therapies.
  • By focusing on molecular and cellular changes
    that are specific to cancer, targeted cancer
    therapies may be more effective than current
    treatments and less harmful to normal cells.

(http//www.cancer.gov/cancertopics/factsheet/Ther
apy/targeted)
8
Poster Child for Targeted Therapies
Imatinib (Gleevec)
  • Prototypical targeted agent is imatinib
  • A selective inhibitor of BCR-Abl tyrosine kinase
    in CML or c-Kit in GIST

9
Chronic Myelogenous Leukemia and the Ph Chromosome
  • Abnormal Philadelphia (Ph) chromosome identified
    in most patients with chronic myelogenous
    leukemia (CML)
  • Identified in over 90 of CML, 20 of adult ALL
    and 5 of pediatric ALL patients
  • Piece of chromosome 9 is abnormally linked to
    chromosome 22
  • 922 translocation
  • c-Abl, the cellular homologue of the transforming
    retrovirus oncogene (v-Abl), is located on
    chromosome 9
  • Activation of c-Abl signals the cell to
    proliferate and grow

10
(No Transcript)
11
Targeted Therapy with Imatinib
  • Imatinib is a potent inhibitor of the BCR-Abl and
    the c-Kit tyrosine kinases
  • Generates marked growth inhibition of CML cells
    and Gastrointestinal Stromal Cell Tumors (GIST)
  • Early Phase I data in CML
  • Hematological response in 98 and cytogenetic
    remissions in 13 of patients treated in Phase I
  • Substantial single agent activity in GIST tumors

12
Targeted Therapies Preclinical
Development(adapted from Paoletti 2005)
Characteristic Cytotoxic Agents Targeted Agents
Discovery Cell based, empirical Receptor based screen, rationale
Mechanism Often unknown Basis for screening
Pharmacological Effect Cytotoxic Cytostatic
Specificity Non-selective Selective
Dose and schedule Pulsed, cyclical at MTD Continuous, at tolerable dose
13
Targeted Therapies Phase I Trials(adapted
from Paoletti 2005)
Characteristic Cytotoxic Agents Targeted Agents
Objectives PK, MTD Optimal biological dose (OBD), PK, PK-PD
Disease All types All types or target bearing
Dose Toxicity-guided escalation Biomarker-guided escalation
Endpoints Toxicity, MTD, PK Target inhibition, OBD, PK
Design Dose escalation in small cohorts Dose escalation to target inhibition
14
Components of Non-Clinical Drug Development
  • In vitro studies Cell lines, cell-free systems
    (drug screening)
  • Drug formulation
  • Chemistry, Manufacturing, and Controls Drug
    supply quality
  • In vivo efficacy studies Animal models and proof
    of principle
  • 5. Non-clinical safety studies

15
In Vitro Study Goals Define the Drugs
Pharmacology
  • Molecular mechanism of action and specific drug
    targets
  • Molecular pharmacology
  • Determinants of response
  • Intracellular pharmacodynamics
  • Mechanisms of drug resistance

16
In Vitro Study Systems
  • Cell-free assay for specific molecular effects
  • Enzyme inhibition, receptor blockade, etc.
  • Yeast-based screening in genetically defined
    target
  • Mammalian cell lines (murine, human, etc.)

17
Preclinical PharmacologyIn Vitro Studies of
Cancer Agents (1)
  • Define anticancer effects
  • Growth inhibition, differentiation, apoptosis,
    etc
  • Impact on defined biochemical and molecular
    pathways
  • RNA, DNA and protein biosynthesis, signaling
    kinases, etc
  • Spectrum of antitumor activity
  • Human tumor cell lines

18
Preclinical PharmacologyIn Vitro Studies of
Cancer Agents (2)
  • Cellular uptake and membrane transport
  • MDR, MRP, etc
  • Mechanisms of resistance
  • In vitro drug metabolism
  • P450 isoenzymes
  • Effects on hERG channels (prolonged QT interval
    risk)
  • Preliminary protein binding studies

19
Components of Non-Clinical Drug Development
  • In vitro studies Cell lines, cell-free systems
    (drug screening)
  • Drug formulation
  • Chemistry, Manufacturing, and Controls Drug
    supply quality
  • In vivo efficacy studies Animal models and proof
    of principle
  • 5. Non-clinical safety studies

20
Drug Supply and Formulation
  • Drug supply bulk chemical synthesis, natural
    product isolation, etc.
  • Good Manufacturing Practice (GMP) guidelines for
    pharmaceutical product manufacturing
  • Formulation for clinical delivery of drug
    vehicles for intravenous or other routes of
    administration

21
Drug Supply Issues
  • Paclitaxel source from the bark and wood of the
    Pacific Yew tree
  • Early drug supply limited the amount available
    for initial clinical trials
  • Newer semisynthetic production from the needles
    of the Yew tree (renewable)

22
Drug Formulation Issues
  • Poor water solubility of natural products
  • Paclitaxel formulation in Cremophore EL
    (increased toxicity?)
  • Camptothecin derivatives formulated in a
    dimethylacetamide, polyethylene glycol and
    phosphoric acid vehicle
  • Later formulated as a lipid colloidal dispersion

23
Components of Non-Clinical Drug Development
  • In vitro studies Cell lines, cell-free systems
    (drug screening)
  • Drug formulation
  • Chemistry, Manufacturing, and Controls Drug
    supply quality
  • In vivo efficacy studies Animal models and proof
    of principle
  • 5. Non-clinical safety studies

24
In Vivo Study GoalsAnimal Models
  • Efficacy Proof of therapeutic principle
  • Toxicology Toxicity profile
  • Practical Issues
  • Animal pharmacokinetics and pharmacodynamics
  • Starting dose and schedule for clinical trials

25
Animal ModelsProof of Principle
  • Animal screening is too expensive for routine use
  • Efficacy in animal models of specific disease
    states occurs after in vitro studies
  • Evaluation of therapeutic index
  • Toxicity versus efficacy

26
Ideal Animal Model
  • Validity
  • Selectivity
  • Predictability
  • Reproducibility

There is no perfect tumor model
27
Endostatin An Endogenous Inhibitor of
Angiogenesis and Tumor GrowthO'Reilly et al,
Cell 88277-285 (1997)
28
Animal Models in Cancer
  • Spontaneous tumors
  • Idiopathic
  • Carcinogen-induced
  • Transgenic/gene knockout animals p53, RB, etc
  • Transplanted tumors
  • Animal tumors Lewis lung, S180 sarcoma, etc
  • Human tumor xenografts human tumor lines
    implanted in immunodeficient mice (current NCI
    standard in vivo efficacy testing system)
  • Human tumors growing in vivo in implantable
    hollow fibers

29
Human Tumor Xenografts
  • Athymic nudemice developed in 1960s
  • Mutation in nu gene on chromosome 11
  • Phenotype retarded growth, low fertility, no
    fur, immunocompromised
  • Lack thymus gland, T-cell immunity
  • First human tumor xenograft of colon
    adenocarcinoma by Rygaard Poulson, 1969

30
Athymic Nude Mice
31
Murine Xenograft Sites
  • Subcutaneous tumor (NCI method of choice) with IP
    drug administration
  • Intraperitoneal
  • Intracranial
  • Intrasplenic
  • Renal subcapsule
  • Site-specific (orthotopic) organ inoculation

32
Xenograft Study Endpoints
  • Toxicity Endpoints
  • Drug related death
  • Net animal weight loss
  • Efficacy Endpoints
  • Clonogenic assay
  • Tumor growth assay (corrected for tumor doubling
    time)
  • Treated/control survival ratio
  • Tumor weight change

33
Xenograft Tumor Weight Change
  • Tumor weight change ratio (used by the NCI in
    xenograft evaluation)
  • Defined as treated/control x 100
  • Tumor weight in mg (a x b2)/2
  • a tumor length
  • b tumor width
  • T/C lt 40-50 is considered significant

34
Xenograft Advantages
  • Many different human tumor cell lines
    transplantable
  • Wide representation of most human solid tumors
  • Allows for evaluation of therapeutic index
  • Good correlation with drug regimens active in
    human lung, colon, breast, and melanoma cancers

35
Xenograft Disadvantages
  • Brain tumors difficult to model
  • Different biological behavior, metastases rare
  • Survival not an ideal endpoint death from bulk
    of tumor, not invasion
  • Shorter doubling times than original growth in
    human
  • Less necrosis, better blood supply
  • Difficult to maintain animals due to infection
    risks
  • Host directed therapies (angiogenesis, immune
    modulation) may not be applicable
  • Human vs. murine effects

36
Other Animal Models
  • Orthotopic animal models Tumor cell implantation
    in target organ
  • Metastatic disease models
  • Transgenic Animal Models
  • P53 or other tumor suppressor gene knockout
    animals
  • Endogenous tumor cell development
  • May be of high value for mAb therapies

37
Non-Clinical Efficacy TestingThe FDA
Perspective(J. Leighton, FDA ODAC Meeting, March
13, 2006)
  • Pharmacological activity assessed by models of
    disease are generally of low relevance to safety
    (IND) and efficacy (NDA) decisions
  • Efficacy in vivo and in vitro from non-clinical
    studies may not dependably predict clinical
    efficacy
  • Heterogeneity of disease
  • Interspecies differences in ADME
  • Role of immune system
  • Pharmacology studies are useful for
  • Assessing an appropriate schedule (daily, weekly,
    q3wks)
  • Justification for a drug combination
  • Understanding effect at a molecular target
  • Examine receptor specificity
  • Identifying and evaluating biomarkers

38
Components of Non-Clinical Drug Development
  • In vitro studies Cell lines, cell-free systems
    (drug screening)
  • Drug formulation
  • Chemistry, Manufacturing, and Controls Drug
    supply quality
  • In vivo efficacy studies Animal models and proof
    of principle
  • 5. Non-clinical safety studies

39
Non-Clinical Safety Studies
  • Safety pharmacology
  • Toxicokinetics pharmacokinetic studies
  • Single dose toxicity studies
  • Repeated dose toxicity studies

40
Safety Pharmacology
  • Assessment of drug on vital functions
  • Examples
  • Cardiovascular heart rate, BP, ECG, QT interval
  • Central nervous system locomotor activity,
    coordination, proconvulsive effects, analgesic
    effects
  • Respiratory system respiratory rate, tidal and
    minute volumes
  • Should complete prior to FIH studies
  • May be separate or a component of toxicity studies

41
Pharmacokinetic Toxicokinetic Studies
  • Analytic assay development and testing
  • Preclinical PK/PD efficacy and toxicity
    relationships
  • Initial drug formulation testing
  • Testing of different schedules and routes of
    administration
  • Animal ADME

42
Non-Clinical Toxicology Studies
  • GLP Toxicology is expected
  • Use the clinical schedule, route, and formulation
  • Single dose acute toxicity studies required in 2
    mammalian species prior to FIH studies
  • Classically rat and dog for small molecules
  • Non-human primates for biologicals
  • Repeat dose toxicology required for anticipated
    duration of clinical use for most non-oncology
    agents
  • 3 mo. toxicology for 3 mo. clinical study
  • Recommendations for agents used in the treatment
    of advanced cancer differs

43
Expected Toxicology Testing for Phase I Oncology
Drug Studies(J. Leighton, FDA ODAC Meeting,
March 13, 2006)
Clinical Schedule Preclinical study schedule
Every 21 d Single dose study
Every 14 d 2 doses, 14 d apart
Weekly x 3, week off Weekly x 3
Daily x 5, break Daily x 5
Continuous daily Daily for 28 days
  • Study schedule does not include a a recovery
    period
  • -- 28 day toxicology is generally sufficient for
    DRUG trials
  • extending beyond 28 days

44
Non-Clinical Toxicology Studies For Oncology Drug
Combinations
  • May not be necessary for testing in advanced
    cancer patients
  • May exclude if
  • No PK, PD, or metabolic interactions anticipated
  • Drugs are not packaged as a combination
  • All components well studied individually

45
Single Dose Toxicity Studies
  • Dose escalation study may be an alternative to a
    single dose design
  • Dose range should include maximally tolerated
    dose (MTD) and no adverse effect level (NOAEL)
  • Standard design
  • Early sacrifice at 24 to 48 hr and after 14 days

46
Repeated Dose Toxicity Studies
  • Duration of repeated dose studies related to
    duration of anticipated clinical use
  • Use same schedule and duration
  • Typically 14-28 days
  • Should include recovery group
  • Use can support repeat dose clinical studies

47
Non-Clinical Toxicology Ongoing Endpoints
  • Ongoing
  • Clinical signs, behavior
  • Body weights and food consumption
  • Clinical pathology (in larger species)
  • Hematology
  • Chemistry panels
  • Toxicokinetics
  • End of Study
  • Macroscopic changes at necropsy
  • Organ weights
  • Histopathology of all organs

48
Other Toxicology Studies
  • Local tolerance studies
  • If warranted by route of administration
  • Genotoxicity studies
  • Reproductive Toxicity studies
  • Carcinogenicity studies

49
Genotoxicity studies
  • General
  • Normally done prior to FIH studies, but not
    required prior to phase I studies in oncology
    patients
  • Standard battery of genotoxicity tests required
    prior to initiation of phase II
  • Specific genotoxicity studies
  • In vitro bacterial reverse mutation assays Ames
    test, point mutation test
  • In vitro chromosome damage tests in mammalian
    cells metaphase cell analysis, murine lymphoma
    gene mutation assays
  • In vivo chromosomal damage assays rodent
    micronucleus tests

50
Reproductive Toxicity Studies
  • Men
  • May include in Phase I/II after relevant repeated
    dose toxicity studies
  • Male fertility study should be completed prior to
    initiation of Phase III
  • Women not of childbearing potential
  • May include in clinical trials after relevant
    repeated dose toxicity studies
  • Women of childbearing potential
  • May include in carefully monitored early studies
    with precautions
  • Fertility and embryo-fetal toxicity studies
    should be completed prior to entry of women into
    phase III trials
  • Pregnant women
  • All reproductive toxicity and genotoxicity
    studies must be completed prior to entry of these
    women in trials

51
Carcinogenicity studies
  • Usually not needed prior to clinical trial
    initiation
  • Not needed in advanced cancer indications

52
Preclinical ToxicologyGoals
  • Estimate a safe starting dose for phase I
    studies
  • Determine the toxicity profile for acute and
    chronic administration
  • NCI guidelines recommend single dose and
    multidose toxicity in two species (one
    non-rodent)
  • Historical guidelines are 1/10 the LD10 in mice
  • Death, as an endpoint no longer required

53
Current FDA Approach to Starting Doses
  • Starting dose of 1/10 the dose causing severe
    toxicity (or death) in 10 of rodents (STD10) on
    mg/m2 basis
  • Provided the same dose causes no severe
    irreversible toxicity in a non-rodent species
    (usually dogs)
  • If irreversible toxicities are seen, then 1/6 of
    the highest dose tested in non-rodents that does
    not cause severe, irreversible toxicity
  • Occasionally, species specific difference may
    mandate the use of alternative species for
    selection of starting dose

54
Determine dose severely toxic to 10 of rodents
(STD10)
Convert from mg/kg to mg/m2 Mouse x 3 Rat x 6
Guinea-pig x 7.7 Hamster x 4.1
Is 1/10 rodent STD10 (mg/m2) severely toxic
to non-rodents?
NO
YES
Is rodent an inappropriate species? (biochem,
ADME, target, etc)
Determine non-rodent Highest Non-Severely Toxic
Dose (HNSTD)
YES
NO
Is non-rodent inappropriate?
YES
NO
Convert from mg/kg to mg/m2 Dog x 20 Monkey x
10 Rabbit x 11.6
Start Dose 1/6 Non-Rodent HNSTD
Start Dose 1/10 Rodent STD10
55
Non-Clinical Drug Safety Testingfor Summary of
the FDA Perspective(J. Leighton, FDA ODAC
Meeting, March 13, 2006)
  • Conduct 2 pivotal toxicology studies using the
    same schedule, formulation, and route as the
    proposed clinical trial
  • Conduct a rodent study that identifies
    life-threatening doses
  • Conduct a non-rodent study that confirms non-life
    threatening doses have been identified
  • Studies of 28 days should be provided for
    continuous administration
  • Studies for one or several administrations,
    depending on the schedule for intermittent
    schedules
  • Provide full histopathology in one of these
    studies
  • Conduct other studies as needed

56
Non-Clinical Drug Safety TestingSummary of the
FDA Perspective(J. Leighton, FDA ODAC Meeting,
March 13, 2006)
  • Multiple cycles/continuous treatment generally
    acceptable, assuming acceptable safety profile in
    the non-clinical setting
  • Pre-IND meeting with sponsors are encouraged to
    discuss problem areas and provide alternative
    pathways to initiation of the phase I trial
  • Most potential clinical holds resolved through
    discussion with sponsor
  • Guidelines for biologicals (monoclonal
    antibodies, etc) are in preparation but may
    differ from small molecule recommendations

57
An Excellent Resource for Anticancer
Drugs(DeGeorge et al Cancer Chemother Pharmacol
199841173)
Plus numerous FDA guidances at http//www.fda.gov/
cder/Guidance
58
Monoclonal Antibody (mAb) Therapeutics
  • Targeted mAb are distinct from small molecule
    therapeutics
  • Explosion in popularity
  • Higher approval rates in oncology (21 vs. lt5)
  • High specificity, less off target risk
  • Long t1/2 (10-21 days)
  • Novel targets that are difficult or impossible to
    modulate by small molecules
  • Flexible bioengineered design
  • Modulation of functional domains

59
Non-Clinical Toxicology for mAb Therapies
  • mAb present major safety challenges
  • Safety toxicology studies in primates
  • Old world primates most common
  • May exceed primate toxicology resources
  • Chimpanzees in rare specialized cases
  • Primate toxicology may still not predict human
    effects
  • TGN1412 anti CD28 super agonist causes
    non-specific broad T-cell activation in humans
    with catastrophic consequences
  • Transgenic rodents engineered to express human
    target may be selectively employed (knock
    out/knock in animals)
  • Surrogate mAb (mouse equivalent) toxicity and
    efficacy studies to support clinical studies

60
Starting Doses for Biological Therapies
  • Historically, some fraction of the no adverse
    event level (NOAEL)
  • If species specific differences preclude precise
    dose calculations, then
  • Consider estimations of receptor occupancy,
    cellular dose response studies from best
    available models to estimate a Minimum
    Anticipated Biological Effect Level (MABEL)
  • Recommendations for biological therapies are in
    evolution

61
An Example of a Phase I study of a Targeted
Therapy that Incorporates Biomarkers Developed in
Preclinical Development
62
AEE788, A Dual EGFR VEGFR Targeting Agent
  • Oral receptor tyrosine kinase inhibitor
  • A dirty kinase inhibitor
  • 7H-pyrrolo2,3-d pyrimidine derivative
  • Inhibits EGFR and ErbB-2 receptor tyrosine
    kinases with IC50s of 2-6 nM
  • Also inhibits multiple other kinases

63
In Vitro AEE788 Pharmacology
  • Kinase IC50 (uM)
  • EGFR 0.002
  • ErbB2 0.006
  • KDR 0.077
  • HER4 0.059
  • C-Abl 0.052
  • C-Src 0.061
  • RET 0.74
  • Kinase IC50 (uM)
  • C-Kit 0.790
  • C-Met 2.90
  • Flk, Tek gt2
  • IGF-1R gt2
  • PKC-a gt10
  • CDK1/2 gt10

64
AEE788 Study Design
  • Three center N. American/European study
  • C.H. Takimoto, IDD/CTRC, San Antonio
  • J. Baselga, Vall dHebron, Barcelona, Spain
  • A.T. van Oosterom, Catholic University Leuven,
    Belgium
  • Dose escalation design of AEE788 orally on a
    daily dose schedule in advanced cancer patients
  • Standard adult phase I patient population
  • 3-6 patients per dose level allowed
  • Endpoints
  • Determine the MTD and DLT of AEE orally on a
    daily dose schedule
  • Characterize drug pharmacokinetics
  • Extensive pharmacodynamic assessments

65
Dose Levels and DLTs During Cycle 1(Baselga ASCO
2005)
Dose Level, mg Enrolled Pts with DLT, n DLT (n)
25 5 0 --
50 6 0 --
100 5 0 --
150 5 0 --
225 7 0 --
300 7 0 --
400 7 0 --
450 7 0 --
500 6 2 Gr 3 diarrhea (2)
550 9 2 Gr 3 diarrhea (2)
Total 64 4
66
AEE788 Skin Rash
  • Skin rash
  • Any grade 42.7
  • Gr 3 or 4 0
  • Dry skin, fine rash seen at lower dose levels
  • Pustular macular papular skin rash seen at higher
    dose levels (gt225 mg/d)

67
AEE788 Other Toxicities
  • Grade 3 diarrhea (10 pts)
  • Grade 3 fatigue (5 pts)
  • Grade 3 anorexia (4 pts)
  • Grade 3 hyperbilirubinemia (3 pts)
  • No evidence of cardiac toxicity or QTc changes in
    2811 EKGs in 96 pts

68
Delayed Onset Reversible Hepatic Transaminase
Elevation
  • Reversible grade 3 / 4 elevations of AST/ALT at
    doses 300 mg seen in 12 pts
  • Median onset of 99 days (after 4 cycles)
  • Observed in presence and absence of liver
    metastases
  • Total bilirubin generally unaffected
  • Dose and duration of treatment dependent
  • Dosing at 300 mg/d for 4 cycles is problematic

69
AEE788 Efficacy Data
  • 83 Patients treated with doses up to 550 mg
  • One PR in angiosarcoma at 400 mg now completed 5
    cycles
  • 36 of 83 pts (43) with stable disease beyond 2
    cycles
  • Median number of cycles that patients remained on
    study is 2 (range 0.5-14)

70
Planned PD Assessments
  • Skin biopsies in 53 pts
  • Vascular IHC analyses in 32 pts
  • Tumor biopsy IHC data from 15 pts

71
Biopsy samples were evaluated by
immunohistochemistry (IHC) and scored by Hscore.
Hscore ( faint stained cells) ( moderate
stained cells)2 ( strong stained cells)3.
Ki67 was scored by positive cells
--Baselga et al, ASCO 2005
72
Results Skin (basal epidermis) p-EGFR
--Baselga et al, ASCO 2005
73
Pharmacodynamic Modeling
--Baselga et al, ASCO 2005
74
Tumor Biopsy IHC Results (n15)
25 mg Pre-Rx During Rx
550 mg Pre-Rx During Rx
--Baselga et al, ASCO 2005
75
PD Tumor Marker Changes
--Baselga et al, ASCO 2005
76
Pharmacodynamic Findings
  • Inhibition of molecular targets was dose and
    serum concentration dependent with significant
    variablity
  • Active concentration AEE788 (parent) AQM674
    (active metabolite)
  • Tumor pEGFR inhibition (IC50 18 nM) agrees with
    A431 cell line data (IC50 11 nM)
  • Skin PD Potency
  • Test ID80
  • pEGFR/pMAPK 225-250 mg
  • Ki67 50-100 mg
  • Tumor PD Potency (greater than skin)
  • Test ID80
  • pEGFR 150 mg
  • pAkt 100-150 mg
  • Optimal biological dose may be 250 mg(?)

77
AEE788 Phase I Study Conclusions
  • Cycle 1 DLT was grade 3 diarrhea despite
    supportive care at 500-550 mg/d
  • Other toxicities fatigue, nausea, rash,
    anorexia, vomiting, stomatitis
  • Chronic dosing revealed grade 3/4 hepatic
    transaminitis at doses gt300 mg after 4 cycles
  • PK/PD analysis suggests dose 250 mg may
    optimally modulate biological target(s)
  • Further exploration of daily 250 mg dosing and
    alternative schedules is ongoing
  • PK/PD biomarker data highly useful in clinical
    decision making process

78
The Clinical Trial Challenge
  • We stand at the dawn of the post genomic era when
    new targets for novel treatments for human cancer
    are just being discovered and defined
  • Basic research is the engine that drives this
    process
  • Clinical researchers have to take these promising
    agents and test them in the best and most
    efficient ways possible
  • Traditional clinical endpoints, and
  • Molecular target endpoints in clinical studies

79
The Challenge!
Preclinical Pharmacology
Early Phase I Pharmacokinetic Clinical Trials
Clinical Pharmacologist
Traditional animal studies PK/PD Toxicolog
y Molecular targets
Traditional dose and toxicity
endpoints Traditional PK/PD Molecular
and biochemical endpoints
80
New Paradigms for Drug Development in the Post
Genomic Era
  • Expanding role for translational studies in Phase
    I clinical trials
  • Bridge the gap between preclinical pharmacologic
    studies and early clinical trials
  • New molecular and biochemical endpoints are
    essential for cancer prevention and
    antimetastatic agents
  • This is an exciting time to be developing new
    anticancer drugs!

81
New Phase I Paradigms Evolution not Revolution!
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