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March 19, 2002

Overview of Colorectal
Chemoprevention Trials


Bernard Levin, M.D.
The University of Texas M. D. Anderson Cancer Center

Carcinogenesis is a Chronic Disorder:
DysplasiaCarcinoma Sequence

Adapted from Ilyas et al. Eur. J . Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484
5-20 yrs 5-15 yrs
ADENOMA
Normal Mild Moderate Severe Cancer
APC,bcl-2, c-myc
Hypomethylation
COX-2

K-ras SMAD 2
SMAD 4
DCC
p53
Focus of Technology Development
Molecular Targets:
Colorectal Neoplasia Chemoprevention
Key Enzymes
COX-2
Ornithine
decarboxylase
Farnysyl transferase
Matrix
metalloproteinase
Raf kinase
SAM decarboxylase
Cyclin-dependent
kinases
Inducible nitric oxide
synthetase (iNOS)
Genetic Mutations
APC
p53
Growth Factors &
Critical Receptors
VEGF
Vitamin D receptor
EGFR
Retinoid receptors
RARs/RXRs/both
Estrogen receptor
PPAR-gamma or -delta

Anticancer Effect of Aspirin-like Drugs:
COX-Dependent and Independent Mechanisms
Immune Function
Carcinogenesis
Prostaglandins (PGE
2
)
Arachidonic
Acid
Free Radical Production
Carcinogen Activation
Proliferation
Angiogenesis
Apoptosis
COX-2
COX
inhibitor
X
COX-1
Sphingomyelin Ceramide
Non-COX Targets:
+P450s
+PPAR|/
|PPARo,
X
0.65
Polyp/Adenoma Incidence
Polyp/Adenoma Incidence
0 1 2
Estimated Relative Risk Estimated Relative Risk
0.52
0.61
0.49
Aspirin Aspirin
Greenberg 93 Greenberg 93
Suh Suh 93 93
Giovannucci 94 Giovannucci 94
Rodriguez 00 Rodriguez 00
NSAIDs NSAIDs
Logan 93 Logan 93
Martinez 95 Martinez 95
Peleg Peleg 96 96
Sandler Sandler 98 98
Breuer Breuer- -Katchinski Katchinski 00 00
0.36
0.31
0.56
0.6
0.21
Prospective Prospective


Retrospective Retrospective
Cancer Incidence
Cancer Incidence Cancer Incidence
Kune 88 Kune 88
Rosenberg 91 Rosenberg 91
Suh 93 Suh 93 Males Males
Suh 93 Suh 93 Females Females
Peleg 94 Peleg 94
Schreinemachers 94 Schreinemachers 94
Giovannucci 94 Giovannucci 94
Giovannucci 95 Giovannucci 95
Paganini Paganini- -Hill 89, 91, 95 Hill 89, 91, 95
LaVecchia 97 LaVecchia 97
Sturmer 98 Sturmer 98
Neugut Neugut 98 98
Bucher 99 Bucher 99
Garcia Rodriguez 01 Garcia Rodriguez 01
Peleg 96 Peleg 96
Muscat 94 Muscat 94 Females Females
Muscat 94 Muscat 94 Males Males
Mller 94 Mller 94
Pinczowski 94 Pinczowski 94
Bansal 96 Bansal 96
Reeves 96 Reeves 96
Rosenberg 98 Rosenberg 98
Smalley 99 Smalley 99
Collett Collett 99 99
Langham Langham 00 00
0.25
0.50
0.38
0.65
0.32
0 0 1 1 2 2
Estimated Relative Risk Estimated Relative Risk
0.84
0.64
0.45
0.70
0.49
0.6
0.5
0.24
0.54
0.08
0.7
0.32
0.74
0.68
0.56
1.5
1.07
0.57
0.76
Retrospective Retrospective
Prospective Prospective


0 0 1 1 2 2
Thun Thun 91 91 Females Females
Thun Thun 91 91 Males Males
Giovannucci 94 Giovannucci 94
Bansal 96 Bansal 96
Estimated Relative Risk Estimated Relative Risk
0.58
0.6
0.51
0.68
Cancer-Associated Mortality
Cancer Cancer- -Associated Mortality Associated Mortality
Retrospective Retrospective
Prospective Prospective


COX Inhibitors Reduce
Colorectal Carcinogenesis
Observational Data
* P < 0.05; n=12/group
Vehicle 150 500 1500 50
0
5
10
15
20
25
30
35
Late treatment
(days 55-80)
Celecoxib Piroxicam
*
(mg/kg diet)
*
Celecoxib Inhibits Tumor Multiplicity in
the MIN Mouse Model
M
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(
t
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)

10
15
20
25
30
35
Vehicle 500 1500 50
0
5
Early treatment
(days 30-80)
Celecoxib Piroxicam
(mg/kg diet)
*
*
J acoby et al: Cancer Res 60:5040-4, 2000
COX-2 Overexpression in Human Neoplasia
Percentage of Positive Published Studies (n)
Preinvasive
Neoplasia
Invasive
Neoplasia
Oropharynx 33% (3) 100% (2)
Esophagus 80% (5) Barretts 100% (4), AdenoCA
100% (2), SCCA
Stomach 100% (2) 91% (11)
Pancreas 50% (2) 100% (5)
Liver - 100% (5)
Colorectum 87% (8) 100% (19)
Lung 100% (2) NSC 100% (7), NSC
Bladder 100% (1) 100% (2)
Prostate 67% (3) 71% (7)
Cervix 100% (1) 100% (3)
Breast 100% (1) 100% (2)
Retinoblastoma - 100% (1)
CNS - 100% (4)
Skin 100% (1) 100% (2)
Total 79% (23/29) 96% (71/74)
Anderson WF, et al: Curr Pharm Design, 8:99-110, 2002
Effect of COX-2 Selective Inhibition on
Colorectal Adenomas in Patients with FAP
Steinbach et al, NEJ M, 2000
Potential Endpoints
Clinical
Adenoma number
Adenoma size
Cumulative lesion
burden
ACF number/size
Cellular
Proliferation
Apoptosis
Molecular
COX-2 expression
CYP-2C9
polymorphisms
Genomic microarray
Proteomic array
Biochemical
Prostanoid
concentrations
Cytokines
No. expected without
polypectomy from
Mayo Clinic data
National Polyp Study: Adenomas as
Reasonable Surrogates of Colorectal Cancer
0
1
2
3
4
5
0 1 2 3 4 5 6 7
8
Years of Follow-up
C
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o
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e
c
t
a
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C
a
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c
e
r

(
%
)

No. observed post polypectomy
No. expected with mixed
intervention from SEER data
No. expected without
polypectomy from
St. Marks data
Winawer SJ , et al. N Engl J Med 329: 19771981, 1993
Current Secondary Prevention of
Sporadic Adenoma Trials
International, multi-center
Placebo controlled
Secondary prevention of
sporadic colorectal adenomas

Secondary Prevention of Colorectal Adenomas:
The Rofecoxib Study
Start date 4/2000
2,000 pts from 110 centers
Rofecoxib 25 mg qd vs. placebo
Colonoscopy after 1 and 3 yr
Primary end point: number of
adenomas
Secondary Prevention of Colorectal Adenomas:
The NCI Study
Start date 12/1999
1,950 pts from 100 centers
Celecoxib 200 bid, 400 bid vs. placebo
Colonoscopy after 1 and 3 yr
Primary end point: number of
adenomas
Secondary Prevention of Colorectal Adenomas:
The PRESAP Study
Start date 3/2001
1500 pts
Celecoxib 400 mg qd vs. placebo
Colonoscopy after 1 and 3 years
Primary end point: number of
adenomas
PRESAP Study Objective
Primary Objective
Evaluate whether celecoxib is safe and effective in
reducing the occurrence of new adenomatous
polyps in subjects who have previously undergone
a polypectomy
Secondary Objectives
Number of colorectal adenomas
Histopathologic grade of colorectal adenomas
Size of colorectal adenomas following
1 and 3 years of study drug treatment
PRESAP Study
Inclusion Criteria
Age 30 or older
Photographed cecum
> 6 mm adenoma (single)
> 1 polyp (any size)
Abstains from NSAIDs or COX-2
inhibitors (low dose ASA allowed)
PRESAP Study
Stratification for Low-Dose Aspirin Use
Celecoxib Placebo
ASA Use
Non-ASA Use
Placebo Celecoxib
Double-Blind
Randomization Period
Single-Blind
Placebo
Lead-In Period
30 Days
(1 Month)
Lead-In
Visit
Month 1
(Randomization)
Begin Study
Drug Treatment
Surveillance
Colonoscopy
Year 1
(Month 13)
Month 38
Phone
Contact
Year 3
(Month 37)
Surveillance
Colonoscopy
End
Treatment
PRESAP Study Timeline Overview
90 Days
Colonoscopy/
Polypectomy
120 Days
Opportunities for Serial Pharmacologic
Synergies in the COX Metabolic Pathway

Nimesulide
(Helsinn)
CDDO
Ursolic Acid
LM4108
(Vanderbilt Univ)
NS398
(Cayman Chemical/
Taisho Pharmaceutical)
JTE 522
(Japan Tobacco)
Meloxicam
(Boehringer Ingelheim)
Nabumetone
(Smith Klein Beecham)
Rofecoxib
(Merck & Co)
Colorectal Neoplasia
Prevention Drug
Development as of
February 2002 (NCI)
P54
(Phytochemicals
Reksa)
Curcumin
(NCI)
Celecoxib
(Pharmacia & NCI)
COX
Inhibitors:
Lovastatin
(Merck & Co)
Marimastat
(British Biotech)
Piromastat
(Agouron)
EKB-569
(Wyeth Ayerst)
GED
(Inotek)
Sulindac
Sulfone
(Cell Pathways)
Selenium
(NCI)
Calcium
Ursodiol
(Novartis & NCI)
Other
Agents:
Phase
I/II
Phase
III
Phase
IV
Preclinical
Aspirin
(NCI)
Inulin
(Orafti)

Sulindac
+ DFMO
(NCI & ILEX)
Celecoxib
+ DFMO
(NCI & ILEX)
Cooperative Efficacy of
COX Inhibitors + DFMO in Animal Models of
Colorectal Cancer Prevention
Investigator Placebo NSAID DFMO Combination

Nigro 1986 3.4 3.2 (6%) 2.1 (38%)* 1.0 (71%)*
Reddy 1990 0.73 0.37 (49%)* 0.30 (59%)* 0.17 (77%)*
Rao 1991 1.14 0.31 (73%)* 0.22 (81%)* 0.08 (93%)*
Li 1999 1.6 1.5 (6%) 0.5 (69%)* 0.3 (81%)*
Jacoby 2000 10.4 2.5 (76%)* 3.7 (64%)* 0.8 (92%)*
Absolute incidence or multiplicity (and percent reduction) in CR neoplasia at study termination

Typically testing each compound at ~50% of the single-agent dose


*Statistically significant vs. placebo, p<0.05
NCI-sponsored Clinical Colorectal
Prevention Trials with COX-2 Inhibitors
Investigator Cohort Agent(s) Primary Goal Phase
Steinbach* FAP Celecoxib Adenoma
regression
II/III
Sinicrope FAP Celecoxib +
DFMO
Adenoma
regression
II/III
Lynch FAP Celecoxib Adenoma
suppression
II/III
Lynch

HNPCC Celecoxib Mucosal
biomarkers
II
Bertagnolli Sporadic Celecoxib Adenoma
prevention
III
Alberts Sporadic Celecoxib +
selenium
Adenoma
prevention
III
*Complete
Closed to
accrual
NCI-sponsored Clinical Extracolonic
Prevention Trials with COX-2 Inhibitors
Investigator Cohort Agent(s) Primary Goal Phase
Forastiere Barretts
dysplasia
Celecoxib Dysplasia
regression
II
Dong &
Dawsey

Esophageal
squamous
dysplasia
Celecoxib +
selenium
Dysplasia
regression
II
Carducci Prostate
cancer
Celecoxib PIN
regression
II
Sabichi Superficial
bladder
cancer
Celecoxib Cancer
recurrence
II/III
Elmets Aktinic
keratosis
Celecoxib AK
regression
II/III
Epstein BCNS Celecoxib Lesional
recurrence
II
Closed to
accrual
NCI-sponsored Clinical Extracolonic
Prevention Trials with COX-2 Inhibitors
Investigator Cohort Agent(s) Primary Goal Phase
Mao Resected
lung cancer
Celecoxib Dysplasia
regression
II
Kurie

Lung
dysplasia
Celecoxib Biomarker
modulation
II
Fabian Breast
cancer risk
Celecoxib Biomarker
modulation
II
Kirsch Rectal ACF Celecoxib ACF
regression &
prevention
II
TBD MGUS Celecoxib Biomarker
modulation
II
Boyle Oral
leukoplakia
Celecoxib Lesional
regression
II
Possible Roles for a
Chemopreventive Agent in
Management of Colorectal Neoplasia
Delay or complement initial
screening
Complement endoscopic
surveillance
Improve effectiveness
10-15% polyp miss rate
5-40% flat adenomas
Reduce procedure-related
morbidities and
inconveniences
Time
Sedation
Complications
Prolong inter-exam intervals
Spare or delay primary
prophylactic polypectomy or
colectomy
Reduce or delay the need for
secondary colorectal
surgeries
Inhibit or retard extracolonic
neoplasia
FAP - duodenal,
desmoids
HNPCC - GU, uterine,
upper GI
Sporadic
Inhibit or retard several age-
related diseases
Improve quality of life
Reduce neoplasia incidence & mortality
Tensions to be Considered in
Absolute vs. Reasonable Medical Assurance
Scientific Rigor
Accuracy
Reproducibility
Quantitiation
Predictive assurance

Scientific Practicality
Time
Patients/staff
Finances
Dynamic landscape

Once the determinants of disease risk are understood, management of those
risks rather than fulminant disease alone creates a clinical dilemma
wherein harm may result from errors of interventional omission or
comission (i.e., risk itself, may become a disease worthy of intervention).
Intermediate Endpoints in CV Prevention

This committee previously recommended,
and the Food and Drug Administration
concurred, that approval of lipid altering
agents should be based on a drugs
biochemical efficacy in decreasing serum
lipids. Attempts to establish clinical efficacy
in the prevention of coronary artery disease
or other manifestations of atherosclerosis,
would require prolonged observations and
hamper research and development of this
class of drugs.
FDA Endocrinologic and Metabolic Drugs Advisory Committee, October 15, 1981
Chemopreventive Drug Development in
Populations at Risk for Colorectal Cancer
General Population:
40% incidence of adenomas;
130,000 CRC cases/yr
Lifetime risk ~ 5.6% (2000)
Moderate Risk:
Current/prior adenoma(s),
cancer survivor,
Lifetime risk ~ 10-20%
High Risk:
FAP, HNPCC, IBD
Lifetime risk ~ 40-100%
Celecoxib
NSAID + DFMO (HD)
NSAID + MMPI
NSAID + EGFR inhibitor
Celecoxib Ursodiol
DFMO Calcium


MMPI Folate/B12*


EGFR inhibitor Selenium
Aspirin*

/curcumin Inulin
NSAID + DFMO (LD)
Calcium

Selenium
Folate/B12*

ASA*

/curcumin
P. activity*

High F&V/low fat*

Inulin
*Active against many cancers
Active against many age-related diseases (e.g., CV, CA, Alzheimers)
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AACR Taskforce Working Conclusion
In CRC risk reduction trials, the adenoma is a
disease endpoint (i.e., a point of clinical intervention
and risk)
Goal = ~ 30% relative reduction in adenoma
incidence
Other potential clinical benefits
Decrease in number of polypectomies and/or procedure-
related risks
Delay in time to adenomas with malignant potential (i.e.,
advanced adenomas)
Increase intervals between surveillance procedures
Organ preservation/delay in time to resection (FAP)
OShaughnessy JA: Clin Cancer Res 8:314-347, 2002