Transcript Non-Clinical Drug Development Chris H. Takimoto, MD, PhD

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
Drug Development
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Drug discovery & screening
Non-clinical development
Animal scale up
Phase I studies
Phase II studies
Phase III studies
Specific examples from anticancer drug development
Overview of Anticancer Drug
Development
NDA
IND
Chemical Synthesis and Formulation Development
Animal Models
for Efficacy
Assay
Development
Animal PK and
PD
Dose
Escalation
and Initial PK
Proof of
Concept and
Dose Finding
Large Efficacy
Trials
with PK Screen
PK/PD Studies in Special Populations
PHASE I
Pre-Clinical Development
PHASE II
PHASE III
Clinical Development
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
Oncology drug development is
changing in the new era of
targeted cancer therapies
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outdated, outmoded, and poorly-suited to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!
What are Targeted Therapies?
The NCI’s Definition
• From the NCI’s 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/Therapy/targeted)
Poster Child for Targeted Therapies
N
H
N
N
N
H
N
N
O
CH3SO3H
Imatinib
Imatinib(Gleevec™)
(Gleevec™)
N
• Prototypical targeted agent is imatinib
• A selective inhibitor of BCR-Abl tyrosine
kinase in CML or c-Kit in GIST
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
– 9:22 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
Targeted Therapy with
Imatinib
• Imatinib is a potent inhibitor of the BCRAbl 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
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
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 Dose escalation to
cohorts
target inhibition
Components of Non-Clinical
Drug Development
1. In vitro studies: Cell lines, cell-free
systems (drug screening)
2. Drug formulation
3. Chemistry, Manufacturing, and
Controls: Drug supply & quality
4. In vivo efficacy studies: Animal
models and proof of principle
5. Non-clinical safety studies
In Vitro Study Goals: Define the
Drug’s Pharmacology
• Molecular mechanism of action and
specific drug targets
• Molecular pharmacology
• Determinants of response
• Intracellular pharmacodynamics
• Mechanisms of drug resistance
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.)
Preclinical Pharmacology
In 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
Preclinical Pharmacology
In 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
Components of Non-Clinical
Drug Development
1. In vitro studies: Cell lines, cell-free
systems (drug screening)
2. Drug formulation
3. Chemistry, Manufacturing, and
Controls: Drug supply & quality
4. In vivo efficacy studies: Animal
models and proof of principle
5. Non-clinical safety studies
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
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)
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
Components of Non-Clinical
Drug Development
1. In vitro studies: Cell lines, cell-free
systems (drug screening)
2. Drug formulation
3. Chemistry, Manufacturing, and
Controls: Drug supply & quality
4. In vivo efficacy studies: Animal
models and proof of principle
5. Non-clinical safety studies
In Vivo Study Goals:
Animal Models
• Efficacy: Proof of therapeutic
principle
• Toxicology: Toxicity profile
• Practical Issues:
– Animal pharmacokinetics and
pharmacodynamics
– Starting dose and schedule for clinical
trials
Animal Models
Proof 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
Ideal Animal Model
• Validity
• Selectivity
• Predictability
• Reproducibility
“There is no perfect tumor model”
Endostatin: An Endogenous Inhibitor
of Angiogenesis and Tumor Growth
O'Reilly et al, Cell 88:277-285 (1997)
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
Human Tumor Xenografts
• Athymic “nude”mice developed in 1960’s
• 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
Athymic Nude Mice
Murine Xenograft Sites
• Subcutaneous tumor (NCI method of
choice) with IP drug administration
• Intraperitoneal
• Intracranial
• Intrasplenic
• Renal subcapsule
• Site-specific (orthotopic) organ
inoculation
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
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 < 40-50% is considered
significant
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
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
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
Non-Clinical Efficacy Testing
The 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
Components of Non-Clinical
Drug Development
1. In vitro studies: Cell lines, cell-free
systems (drug screening)
2. Drug formulation
3. Chemistry, Manufacturing, and
Controls: Drug supply & quality
4. In vivo efficacy studies: Animal
models and proof of principle
5. Non-clinical safety studies
Non-Clinical Safety Studies
• Safety pharmacology
• Toxicokinetics & pharmacokinetic
studies
• Single dose toxicity studies
• Repeated dose toxicity studies
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
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
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
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
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
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
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
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
Other Toxicology Studies
• Local tolerance studies
– If warranted by route of administration
• Genotoxicity studies
• Reproductive Toxicity studies
• Carcinogenicity studies
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
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
Carcinogenicity studies
• Usually not needed prior to clinical
trial initiation
• Not needed in advanced cancer
indications
Preclinical Toxicology
Goals
• 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
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
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
Is rodent an
inappropriate species?
(biochem, ADME, target, etc)
YES
Determine non-rodent Highest
Non-Severely Toxic Dose
(HNSTD)
YES
NO
YES
Is non-rodent inappropriate?
NO
Convert from mg/kg to mg/m2
Dog x 20; Monkey x 10
Rabbit x 11.6
Start Dose =1/10
Rodent STD10
Start Dose =1/6
Non-Rodent HNSTD
Non-Clinical Drug Safety Testing
for 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
Non-Clinical Drug Safety Testing
Summary 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
An Excellent Resource for Anticancer Drugs
(DeGeorge et al Cancer Chemother Pharmacol 1998;41:173)
Plus numerous FDA guidances at http://www.fda.gov/cder/Guidance
Monoclonal Antibody (mAb)
Therapeutics
• Targeted mAb are distinct from small molecule
therapeutics
– Explosion in popularity
– Higher approval rates in oncology (~21% vs. <5%)
• 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
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
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
An Example of a Phase I study of
a Targeted Therapy that
Incorporates Biomarkers
Developed in Preclinical
Development
AEE788, A Dual EGFR &
VEGFR Targeting Agent
N
HN
N
N
N
H
N
• Oral receptor tyrosine kinase inhibitor
– A “dirty” kinase inhibitor
• 7H-pyrrolo[2,3-d] pyrimidine derivative
• Inhibits EGFR and ErbB-2 receptor tyrosine kinases with
IC50’s of 2-6 nM
• Also inhibits multiple other kinases
In Vitro AEE788 Pharmacology
Kinase
EGFR
ErbB2
KDR
HER4
C-Abl
C-Src
RET
IC50 (uM)
0.002
0.006
0.077
0.059
0.052
0.061
0.74
Kinase
C-Kit
C-Met
Flk, Tek
IGF-1R
PKC-a
CDK1/2
IC50 (uM)
0.790
2.90
>2
>2
>10
>10
AEE788 Study Design
• Three center N. American/European study
– C.H. Takimoto, IDD/CTRC, San Antonio
– J. Baselga, Vall d’Hebron, 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
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
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 (>225 mg/d)
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
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
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)
Planned PD Assessments
Cycle 1
AEE788
w1
w2
Cycle 2
w3
w4
w5
Daily
Skin biopsy
day-8
Skin (wound) biopsy
day -1
Tumor biopsy
day -14 to -1
Skin biopsy
day +22
Skin (wound) biopsy
day +29
Tumor biopsy
day +28
• Skin biopsies in 53 pts
• Vascular IHC analyses in 32 pts
• Tumor biopsy IHC data from 15 pts
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
Results: Skin (basal epidermis) p-EGFR
120
150
150
150
105
100
120
120
120
120
105
90
90
88
105
80
90
75
73
75
73
60
60
59
75
60
60
78
75
75
75
60
60
48
45
90
60
60
60
42
40
42
30
30
30
30
30
30
20
15
12
0
Hscore basal pEGFR day -7
Hscore basal pEGFR day +22
0
Hscore basal pEGFR day -7
25mg
Hscore basal pEGFR day +22
Hscore basal pEGFR day -7
50mg
15
0
0
Hscore basal pEGFR day -7
Hscore basal pEGFR day +22
100mg
150mg
150
150
150
150
120
120
120
120
90
90
90
90
75
72
Hscore basal pEGFR day +22
72
72
66
60
60
54
60
60
54
60
48
45
42
36
30
30
28
30
15
17
15
30
30
24
15
12
6
0
0
Hscore basal pEGFR day -7
Hscore basal pEGFR day +22
225mg
Hscore basal pEGFR day -7
Hscore basal pEGFR day +22
300mg
30
30
0
0
Hscore basal pEGFR day -7
Hscore basal pEGFR day +22
400mg
30
0
0
Hscore basal pEGFR day -7
Hscore basal pEGFR day +22
550mg
--Baselga et al, ASCO 2005
Pharmacodynamic Modeling
--Baselga et al, ASCO 2005
Tumor Biopsy IHC Results (n=15)
pEGFR
pMAPK
pAkt
Ki67
25 mg
Pre-Rx
During Rx
550 mg
Pre-Rx
During Rx
--Baselga et al, ASCO 2005
PD Tumor Marker Changes
Maximal pEGFR Suppression
--Baselga et al, ASCO 2005
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(?)
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 >300 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
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
The Challenge!
Preclinical
Pharmacology
Clinical
Pharmacologist
Traditional animal
studies
PK/PD
Toxicology
Molecular targets
Early Phase I
Pharmacokinetic
Clinical Trials
Traditional dose and
toxicity endpoints
Traditional PK/PD
Molecular and
biochemical
endpoints
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!
New Phase I Paradigms:
Evolution not Revolution!