march 19, 2002 overview of colorectal chemoprevention trials bernard levin, m.d. the university of...
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March 19, 2002March 19, 2002
Overview of Colorectal Overview of Colorectal
Chemoprevention TrialsChemoprevention Trials
Bernard Levin, M.D.Bernard Levin, M.D.The University of Texas M. D. Anderson Cancer CenterThe University of Texas M. D. Anderson Cancer Center
March 19, 2002March 19, 2002
Overview of Colorectal Overview of Colorectal
Chemoprevention TrialsChemoprevention Trials
Bernard Levin, M.D.Bernard Levin, M.D.The University of Texas M. D. Anderson Cancer CenterThe University of Texas M. D. Anderson Cancer Center
Carcinogenesis is a Chronic Disorder:Dysplasia–Carcinoma Sequence
Carcinogenesis is a Chronic Disorder:Dysplasia–Carcinoma Sequence
Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484 Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484
5-20 yrs5-20 yrs 5-15 yrs5-15 yrsADENOMAADENOMA
Normal Mild Moderate Severe Cancer
APC,bcl-2, c-mycHypomethylation
COX-2COX-2
APC,bcl-2, c-mycHypomethylation
COX-2COX-2
K-rasK-ras SMAD 2SMAD 4DCC
SMAD 2SMAD 4DCC
p53p53
Focus of Technology DevelopmentFocus of Technology Development
Molecular Targets:Colorectal Neoplasia Chemoprevention
Molecular Targets:Colorectal Neoplasia Chemoprevention
• Key EnzymesKey Enzymes– COX-2COX-2– Ornithine Ornithine
decarboxylasedecarboxylase– Farnysyl transferaseFarnysyl transferase– Matrix Matrix
metalloproteinasemetalloproteinase– Raf kinase Raf kinase – SAM decarboxylaseSAM decarboxylase– Cyclin-dependent Cyclin-dependent
kinaseskinases– Inducible nitric oxide Inducible nitric oxide
synthetase (iNOS)synthetase (iNOS)
• Key EnzymesKey Enzymes– COX-2COX-2– Ornithine Ornithine
decarboxylasedecarboxylase– Farnysyl transferaseFarnysyl transferase– Matrix Matrix
metalloproteinasemetalloproteinase– Raf kinase Raf kinase – SAM decarboxylaseSAM decarboxylase– Cyclin-dependent Cyclin-dependent
kinaseskinases– Inducible nitric oxide Inducible nitric oxide
synthetase (iNOS)synthetase (iNOS)
• Genetic MutationsGenetic Mutations– APCAPC– p53p53
• Growth Factors & Growth Factors & Critical ReceptorsCritical Receptors– VEGFVEGF– Vitamin D receptorVitamin D receptor– EGFREGFR– Retinoid receptorsRetinoid receptors
– RARs/RXRs/bothRARs/RXRs/both– Estrogen receptor Estrogen receptor – PPAR-gamma or -deltaPPAR-gamma or -delta
• Genetic MutationsGenetic Mutations– APCAPC– p53p53
• Growth Factors & Growth Factors & Critical ReceptorsCritical Receptors– VEGFVEGF– Vitamin D receptorVitamin D receptor– EGFREGFR– Retinoid receptorsRetinoid receptors
– RARs/RXRs/bothRARs/RXRs/both– Estrogen receptor Estrogen receptor – PPAR-gamma or -deltaPPAR-gamma or -delta
Anticancer Effect of Aspirin-like Drugs:COX-Dependent and Independent Mechanisms
Anticancer Effect of Aspirin-like Drugs:COX-Dependent and Independent Mechanisms
Immune FunctionImmune Function
CarcinogenesisCarcinogenesis
Prostaglandins (PGEProstaglandins (PGE22))
ArachidonicArachidonicAcidAcid
Free Radical ProductionFree Radical ProductionCarcinogen ActivationCarcinogen Activation
ProliferationProliferation
AngiogenesisAngiogenesis
ApoptosisApoptosis
COX-2COX-2COXCOX
inhibitorinhibitorCOXCOX
inhibitorinhibitor XXXXCOX-1COX-1
SphingomyelinSphingomyelin CeramideCeramide
Non-COX Targets:Non-COX Targets:P450sP450sPPARPPAR//PPARPPAR,,
XX
0.65
Polyp/Adenoma IncidencePolyp/Adenoma Incidence
0 1 2Estimated Relative RiskEstimated Relative Risk
0.52
0.61
0.49
AspirinAspirin
Greenberg ‘93Greenberg ‘93
SuhSuh ‘93‘93
Giovannucci ‘94Giovannucci ‘94
Rodriguez ‘00Rodriguez ‘00
NSAIDsNSAIDs
Logan ‘93Logan ‘93
Martinez ‘95Martinez ‘95
PelegPeleg ‘96‘96
SandlerSandler ‘98‘98
BreuerBreuer--Katchinski Katchinski ‘00‘00
0.36
0.31
0.56
0.6
0.21
ProspectiveProspective•••• RetrospectiveRetrospective
Cancer IncidenceCancer IncidenceCancer IncidenceKune ‘88Kune ‘88
Rosenberg ‘91Rosenberg ‘91Suh ‘93 Suh ‘93 –– MalesMales
Suh ‘93 Suh ‘93 –– FemalesFemalesPeleg ‘94Peleg ‘94
Schreinemachers ‘94Schreinemachers ‘94Giovannucci ‘94Giovannucci ‘94Giovannucci ‘95Giovannucci ‘95
PaganiniPaganini--Hill ‘89, ‘91, ‘95Hill ‘89, ‘91, ‘95LaVecchia ‘97LaVecchia ‘97
Sturmer ‘98Sturmer ‘98NeugutNeugut ‘98‘98Bucher ‘99Bucher ‘99
Garcia Rodriguez ‘01Garcia Rodriguez ‘01Peleg ‘96Peleg ‘96
Muscat ‘94 Muscat ‘94 –– FemalesFemalesMuscat ‘94 Muscat ‘94 –– MalesMales
Müller ‘94Müller ‘94Pinczowski ‘94Pinczowski ‘94
Bansal ‘96Bansal ‘96Reeves ‘96Reeves ‘96
Rosenberg ‘98Rosenberg ‘98Smalley ‘99Smalley ‘99
Collett Collett ‘99‘99Langham Langham ‘00‘00
0.25
0.50
0.38
0.65
0.32
00 11 22
Estimated Relative RiskEstimated Relative Risk
0.84
0.64
0.45
0.700.49
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
RetrospectiveRetrospectiveProspectiveProspective••
••
00 11 22
ThunThun ‘91 ‘91 –– FemalesFemales
ThunThun ‘91 ‘91 –– MalesMales
Giovannucci ‘94Giovannucci ‘94
Bansal ‘96Bansal ‘96
Estimated Relative RiskEstimated Relative Risk
0.58
0.6
0.51
0.68
Cancer-Associated MortalityCancerCancer--Associated MortalityAssociated Mortality
RetrospectiveRetrospectiveProspectiveProspective••
••
COX Inhibitors Reduce Colorectal Carcinogenesis
– Observational Data
COX Inhibitors Reduce Colorectal Carcinogenesis
– Observational Data
* P < 0.05; n=12/group* P < 0.05; n=12/group
VehicleVehicle 150150 500500 15001500 505000
55
1010
1515
2020
2525
3030
3535 Late treatment(days 55-80)
CelecoxibCelecoxib PiroxicamPiroxicam
*
(mg/kg diet)(mg/kg diet)
*
Celecoxib Inhibits Tumor Multiplicity in Celecoxib Inhibits Tumor Multiplicity in
the MIN Mouse Modelthe MIN Mouse Model
Celecoxib Inhibits Tumor Multiplicity in Celecoxib Inhibits Tumor Multiplicity in
the MIN Mouse Modelthe MIN Mouse Model
Mu
ltip
lici
ty (
tum
ors
/an
imal
)
1010
1515
2020
2525
3030
3535
VehicleVehicle 500500 15001500 505000
55
Early treatment(days 30-80)
CelecoxibCelecoxib PiroxicamPiroxicam(mg/kg diet)(mg/kg diet)
**
Jacoby et al: Cancer Res 60:5040-4, 2000Jacoby et al: Cancer Res 60:5040-4, 2000
COX-2 Overexpression in Human NeoplasiaCOX-2 Overexpression in Human NeoplasiaCOX-2 Overexpression in Human NeoplasiaCOX-2 Overexpression in Human NeoplasiaPercentage of “Positive” Published Studies (n)Percentage of “Positive” Published Studies (n)
Preinvasive Preinvasive NeoplasiaNeoplasia
Invasive Invasive NeoplasiaNeoplasia
OropharynxOropharynx 33% (3)33% (3) 100% (2)100% (2)
EsophagusEsophagus 80% (5) Barrett’s 80% (5) Barrett’s 100% (4), AdenoCA 100% (4), AdenoCA
100% (2), SCCA100% (2), SCCA
StomachStomach 100% (2)100% (2) 91% (11)91% (11)
PancreasPancreas 50% (2)50% (2) 100% (5)100% (5)
LiverLiver -- 100% (5)100% (5)
ColorectumColorectum 87% (8)87% (8) 100% (19)100% (19)
LungLung 100% (2) NSC100% (2) NSC 100% (7), NSC100% (7), NSC
BladderBladder 100% (1)100% (1) 100% (2)100% (2)
ProstateProstate 67% (3)67% (3) 71% (7)71% (7)
CervixCervix 100% (1)100% (1) 100% (3)100% (3)
BreastBreast 100% (1)100% (1) 100% (2)100% (2)
RetinoblastomaRetinoblastoma -- 100% (1)100% (1)
CNSCNS -- 100% (4)100% (4)
SkinSkin 100% (1)100% (1) 100% (2)100% (2)
TotalTotal 79% (23/29)79% (23/29) 96% (71/74)96% (71/74)
Anderson WF, et al: Curr Pharm Design, 8:99-110, 2002Anderson WF, et al: Curr Pharm Design, 8:99-110, 2002
Effect of COX-2 Selective Inhibition on Colorectal Adenomas in Patients with FAP
Effect of COX-2 Selective Inhibition on Colorectal Adenomas in Patients with FAP
Steinbach et al, NEJM, 2000Steinbach et al, NEJM, 2000
Potential EndpointsPotential EndpointsPotential EndpointsPotential Endpoints
ClinicalClinical
• Adenoma numberAdenoma number
• Adenoma sizeAdenoma size
• Cumulative lesion Cumulative lesion burdenburden
• ACF number/sizeACF number/size
CellularCellular
• ProliferationProliferation
• ApoptosisApoptosis
ClinicalClinical
• Adenoma numberAdenoma number
• Adenoma sizeAdenoma size
• Cumulative lesion Cumulative lesion burdenburden
• ACF number/sizeACF number/size
CellularCellular
• ProliferationProliferation
• ApoptosisApoptosis
MolecularMolecular
• COX-2 expressionCOX-2 expression
• CYP-2C9 polymorphismsCYP-2C9 polymorphisms
• Genomic microarrayGenomic microarray
• Proteomic arrayProteomic array
BiochemicalBiochemical
• Prostanoid Prostanoid concentrations concentrations
• CytokinesCytokines
MolecularMolecular
• COX-2 expressionCOX-2 expression
• CYP-2C9 polymorphismsCYP-2C9 polymorphisms
• Genomic microarrayGenomic microarray
• Proteomic arrayProteomic array
BiochemicalBiochemical
• Prostanoid Prostanoid concentrations concentrations
• CytokinesCytokines
No. expected withoutNo. expected withoutpolypectomy frompolypectomy fromMayo Clinic dataMayo Clinic data
National Polyp Study: Adenomas as Reasonable Surrogates of Colorectal Cancer
National Polyp Study: Adenomas as Reasonable Surrogates of Colorectal Cancer
00
11
22
33
44
55
00 11 22 33 44 55 66 77 88
Years of Follow-upYears of Follow-up
Cu
mu
lati
ve I
nci
den
ce o
fC
um
ula
tive
In
cid
ence
of
Co
lore
ctal
Can
cer
(%)
Co
lore
ctal
Can
cer
(%)
No. observed post polypectomyNo. observed post polypectomy
No. expected with mixedNo. expected with mixedintervention from SEER dataintervention from SEER data
No. expected withoutNo. expected withoutpolypectomy frompolypectomy fromSt. Mark’s dataSt. Mark’s data
Winawer SJ, et al. N Engl J Med Winawer SJ, et al. N Engl J Med 329329: 1977—1981, 1993: 1977—1981, 1993
Current Secondary Prevention of Current Secondary Prevention of Sporadic Adenoma TrialsSporadic Adenoma Trials
Current Secondary Prevention of Current Secondary Prevention of Sporadic Adenoma TrialsSporadic Adenoma Trials
• International, multi-centerInternational, multi-center
• Placebo controlledPlacebo controlled
• Secondary prevention ofSecondary prevention ofsporadic colorectal adenomassporadic colorectal adenomas
• International, multi-centerInternational, multi-center
• Placebo controlledPlacebo controlled
• Secondary prevention ofSecondary prevention ofsporadic colorectal adenomassporadic colorectal adenomas
Secondary Prevention of Colorectal Adenomas:Secondary Prevention of Colorectal Adenomas:The Rofecoxib StudyThe Rofecoxib Study
Secondary Prevention of Colorectal Adenomas:Secondary Prevention of Colorectal Adenomas:The Rofecoxib StudyThe Rofecoxib Study
• Start date 4/2000Start date 4/2000
• 2,000 pts from 110 centers2,000 pts from 110 centers
• Rofecoxib 25 mg qd vs. placeboRofecoxib 25 mg qd vs. placebo
• Colonoscopy after 1 and 3 yrColonoscopy after 1 and 3 yr
• Primary end point: number of Primary end point: number of adenomasadenomas
• Start date 4/2000Start date 4/2000
• 2,000 pts from 110 centers2,000 pts from 110 centers
• Rofecoxib 25 mg qd vs. placeboRofecoxib 25 mg qd vs. placebo
• Colonoscopy after 1 and 3 yrColonoscopy after 1 and 3 yr
• Primary end point: number of Primary end point: number of adenomasadenomas
Secondary Prevention of Colorectal Adenomas: Secondary Prevention of Colorectal Adenomas: The NCI StudyThe NCI Study
Secondary Prevention of Colorectal Adenomas: Secondary Prevention of Colorectal Adenomas: The NCI StudyThe NCI Study
• Start date 12/1999Start date 12/1999
• 1,950 pts from 100 centers1,950 pts from 100 centers
• Celecoxib 200 bid, 400 bid vs. placeboCelecoxib 200 bid, 400 bid vs. placebo
• Colonoscopy after 1 and 3 yrColonoscopy after 1 and 3 yr
• Primary end point: number of Primary end point: number of adenomasadenomas
• Start date 12/1999Start date 12/1999
• 1,950 pts from 100 centers1,950 pts from 100 centers
• Celecoxib 200 bid, 400 bid vs. placeboCelecoxib 200 bid, 400 bid vs. placebo
• Colonoscopy after 1 and 3 yrColonoscopy after 1 and 3 yr
• Primary end point: number of Primary end point: number of adenomasadenomas
Secondary Prevention of Colorectal Adenomas: Secondary Prevention of Colorectal Adenomas: The PRESAP StudyThe PRESAP Study
Secondary Prevention of Colorectal Adenomas: Secondary Prevention of Colorectal Adenomas: The PRESAP StudyThe PRESAP Study
• Start date 3/2001 Start date 3/2001
• 1500 pts1500 pts
• Celecoxib 400 mg qd vs. placeboCelecoxib 400 mg qd vs. placebo
• Colonoscopy after 1 and 3 yearsColonoscopy after 1 and 3 years
• Primary end point: number of Primary end point: number of adenomasadenomas
• Start date 3/2001 Start date 3/2001
• 1500 pts1500 pts
• Celecoxib 400 mg qd vs. placeboCelecoxib 400 mg qd vs. placebo
• Colonoscopy after 1 and 3 yearsColonoscopy after 1 and 3 years
• Primary end point: number of Primary end point: number of adenomasadenomas
PRESAP Study ObjectivePRESAP Study ObjectivePRESAP Study ObjectivePRESAP Study Objective
• Primary ObjectivePrimary Objective
– Evaluate whether celecoxib is safe and effective in Evaluate whether celecoxib is safe and effective in reducing the occurrence of new adenomatousreducing the occurrence of new adenomatouspolyps in subjects who have previously undergonepolyps in subjects who have previously undergonea polypectomya polypectomy
• Secondary ObjectivesSecondary Objectives
– Number of colorectal adenomasNumber of colorectal adenomas
– Histopathologic grade of colorectal adenomasHistopathologic grade of colorectal adenomas
– Size of colorectal adenomas followingSize of colorectal adenomas following1 and 3 years of study drug treatment1 and 3 years of study drug treatment
• Primary ObjectivePrimary Objective
– Evaluate whether celecoxib is safe and effective in Evaluate whether celecoxib is safe and effective in reducing the occurrence of new adenomatousreducing the occurrence of new adenomatouspolyps in subjects who have previously undergonepolyps in subjects who have previously undergonea polypectomya polypectomy
• Secondary ObjectivesSecondary Objectives
– Number of colorectal adenomasNumber of colorectal adenomas
– Histopathologic grade of colorectal adenomasHistopathologic grade of colorectal adenomas
– Size of colorectal adenomas followingSize of colorectal adenomas following1 and 3 years of study drug treatment1 and 3 years of study drug treatment
PRESAP Study PRESAP Study Inclusion CriteriaInclusion CriteriaPRESAP Study PRESAP Study
Inclusion CriteriaInclusion Criteria
• Age 30 or olderAge 30 or older
• Photographed cecumPhotographed cecum
6 mm adenoma (single)6 mm adenoma (single)
1 polyp (any size)1 polyp (any size)
• Abstains from NSAIDs or COX-2 Abstains from NSAIDs or COX-2 inhibitors (low dose ASA allowed) inhibitors (low dose ASA allowed)
• Age 30 or olderAge 30 or older
• Photographed cecumPhotographed cecum
6 mm adenoma (single)6 mm adenoma (single)
1 polyp (any size)1 polyp (any size)
• Abstains from NSAIDs or COX-2 Abstains from NSAIDs or COX-2 inhibitors (low dose ASA allowed) inhibitors (low dose ASA allowed)
PRESAP Study PRESAP Study Stratification for Low-Dose Aspirin UseStratification for Low-Dose Aspirin Use
PRESAP Study PRESAP Study Stratification for Low-Dose Aspirin UseStratification for Low-Dose Aspirin Use
CelecoxibCelecoxib CelecoxibCelecoxib PlaceboPlaceboPlaceboPlacebo
ASA UseASA Use Non-ASA UseNon-ASA Use
PlaceboPlaceboPlaceboPlaceboCelecoxib Celecoxib Celecoxib Celecoxib
Double-BlindRandomization 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 OverviewPRESAP Study Timeline OverviewPRESAP Study Timeline OverviewPRESAP Study Timeline Overview
90 Days
Colonoscopy/Polypectomy
120 Days
Opportunities for Serial Pharmacologic Synergies in the COX Metabolic PathwayOpportunities for Serial Pharmacologic
Synergies in the COX Metabolic Pathway
NimesulideNimesulide
(Helsinn)NimesulideNimesulide
(Helsinn)
CDDOCDDOUrsolic AcidUrsolic Acid
CDDOCDDOUrsolic AcidUrsolic Acid
LM4108LM4108(Vanderbilt Univ)
LM4108LM4108(Vanderbilt Univ)
NS398NS398(Cayman Chemical/
Taisho Pharmaceutical)
NS398NS398(Cayman Chemical/
Taisho Pharmaceutical)
JTEJTE 522522(Japan Tobacco)
JTEJTE 522522(Japan Tobacco)
MeloxicamMeloxicam(Boehringer Ingelheim)
MeloxicamMeloxicam(Boehringer Ingelheim)
NabumetoneNabumetone(Smith Klein Beecham)
NabumetoneNabumetone(Smith Klein Beecham)
RofecoxibRofecoxib(Merck & Co)RofecoxibRofecoxib(Merck & Co)
Colorectal NeoplasiaPrevention Drug Development as of February 2002 (NCI)
P54P54(Phytochemicals
Reksa)
Curcumin(NCI)
P54P54(Phytochemicals
Reksa)
Curcumin(NCI)
CelecoxibCelecoxib(Pharmacia & NCI)
CelecoxibCelecoxib(Pharmacia & NCI)
COXInhibitors:
Lovastatin Lovastatin (Merck & Co)
Lovastatin Lovastatin (Merck & Co)
MarimastatMarimastat(British Biotech)
PiromastatPiromastat(Agouron)
EKB-569EKB-569 (Wyeth Ayerst)(Wyeth Ayerst)
GEDGED(Inotek)(Inotek)
MarimastatMarimastat(British Biotech)
PiromastatPiromastat(Agouron)
EKB-569EKB-569 (Wyeth Ayerst)(Wyeth Ayerst)
GEDGED(Inotek)(Inotek)
SulindacSulindac
SulfoneSulfone(Cell Pathways)
SulindacSulindac
SulfoneSulfone(Cell Pathways)
Selenium(NCI)
Selenium(NCI)
CalciumCalciumCalciumCalcium
UrsodiolUrsodiol(Novartis & NCI)
UrsodiolUrsodiol(Novartis & NCI)
OtherAgents:
PhasePhaseI/III/II
PhasePhaseI/III/II
PhasePhaseIIIIII
PhasePhaseIIIIII
PhasePhaseIVIV
PhasePhaseIVIVPreclinicalPreclinicalPreclinicalPreclinical
AspirinAspirin(NCI)(NCI)
AspirinAspirin(NCI)(NCI)
InulinInulin(Orafti)(Orafti)InulinInulin(Orafti)(Orafti)
SulindacSulindac+ DFMO+ DFMO
(NCI & ILEX)(NCI & ILEX)
SulindacSulindac+ DFMO+ DFMO
(NCI & ILEX)(NCI & ILEX)
CelecoxibCelecoxib+ DFMO+ DFMO
(NCI & ILEX)(NCI & ILEX)
CelecoxibCelecoxib+ DFMO+ DFMO
(NCI & ILEX)(NCI & ILEX)
Cooperative Efficacy of Cooperative Efficacy of COX Inhibitors + DFMO in Animal Models of COX Inhibitors + DFMO in Animal Models of
Colorectal Cancer PreventionColorectal Cancer Prevention
Cooperative Efficacy of Cooperative Efficacy of COX Inhibitors + DFMO in Animal Models of COX Inhibitors + DFMO in Animal Models of
Colorectal Cancer PreventionColorectal Cancer Prevention
InvestigatorInvestigator PlaceboPlacebo NSAIDNSAID DFMODFMO CombinationCombination††
Nigro 1986Nigro 1986 3.43.4 3.2 (6%)3.2 (6%) 2.1 (38%)*2.1 (38%)* 1.0 (71%)*1.0 (71%)*
Reddy 1990Reddy 1990 0.730.73 0.37 (49%)*0.37 (49%)* 0.30 (59%)*0.30 (59%)* 0.17 (77%)*0.17 (77%)*
Rao 1991Rao 1991 1.141.14 0.31 (73%)*0.31 (73%)* 0.22 (81%)*0.22 (81%)* 0.08 (93%)*0.08 (93%)*
Li 1999Li 1999 1.61.6 1.5 (6%)1.5 (6%) 0.5 (69%)*0.5 (69%)* 0.3 (81%)*0.3 (81%)*
Jacoby 2000Jacoby 2000 10.410.4 2.5 (76%)*2.5 (76%)* 3.7 (64%)*3.7 (64%)* 0.8 (92%)*0.8 (92%)*
Absolute incidence or multiplicity (and percent reduction) in CR neoplasia at study terminationAbsolute incidence or multiplicity (and percent reduction) in CR neoplasia at study termination††Typically testing each compound at ~50% of the single-agent doseTypically testing each compound at ~50% of the single-agent dose*Statistically significant vs. placebo, p<0.05*Statistically significant vs. placebo, p<0.05
NCI-sponsored Clinical Colorectal NCI-sponsored Clinical Colorectal Prevention Trials with COX-2 InhibitorsPrevention Trials with COX-2 Inhibitors
NCI-sponsored Clinical Colorectal NCI-sponsored Clinical Colorectal Prevention Trials with COX-2 InhibitorsPrevention Trials with COX-2 Inhibitors
InvestigatorInvestigator CohortCohort Agent(s)Agent(s) Primary GoalPrimary Goal PhasePhase
Steinbach*Steinbach* FAPFAP CelecoxibCelecoxib Adenoma Adenoma regressionregression
II/IIIII/III
SinicropeSinicrope FAPFAP Celecoxib + Celecoxib + DFMODFMO
Adenoma Adenoma regressionregression
II/IIIII/III
LynchLynch FAPFAP CelecoxibCelecoxib Adenoma Adenoma suppressionsuppression
II/IIIII/III
LynchLynch†† HNPCCHNPCC CelecoxibCelecoxib Mucosal Mucosal biomarkersbiomarkers
IIII
BertagnolliBertagnolli SporadicSporadic CelecoxibCelecoxib Adenoma Adenoma preventionprevention
IIIIII
AlbertsAlberts SporadicSporadic Celecoxib + Celecoxib + seleniumselenium
Adenoma Adenoma preventionprevention
IIIIII
*Complete*Complete
††Closed to accrualClosed to accrual
NCI-sponsored Clinical Extracolonic NCI-sponsored Clinical Extracolonic Prevention Trials with COX-2 InhibitorsPrevention Trials with COX-2 InhibitorsNCI-sponsored Clinical Extracolonic NCI-sponsored Clinical Extracolonic
Prevention Trials with COX-2 InhibitorsPrevention Trials with COX-2 Inhibitors
InvestigatorInvestigator CohortCohort Agent(s)Agent(s) Primary GoalPrimary Goal PhasePhase
ForastiereForastiere Barrett’s Barrett’s dysplasiadysplasia
CelecoxibCelecoxib Dysplasia Dysplasia regressionregression
IIII
Dong & Dong & DawseyDawsey††
Esophageal Esophageal squamous squamous dysplasiadysplasia
Celecoxib + Celecoxib + seleniumselenium
Dysplasia Dysplasia regressionregression
IIII
CarducciCarducci Prostate Prostate cancercancer
CelecoxibCelecoxib PIN PIN regressionregression
IIII
SabichiSabichi Superficial Superficial bladder bladder cancercancer
CelecoxibCelecoxib Cancer Cancer recurrencerecurrence
II/IIIII/III
ElmetsElmets Aktinic Aktinic keratosiskeratosis
CelecoxibCelecoxib AK AK regressionregression
II/IIIII/III
EpsteinEpstein BCNSBCNS CelecoxibCelecoxib Lesional Lesional recurrencerecurrence
IIII
††Closed to accrualClosed to accrual
NCI-sponsored Clinical Extracolonic NCI-sponsored Clinical Extracolonic Prevention Trials with COX-2 InhibitorsPrevention Trials with COX-2 InhibitorsNCI-sponsored Clinical Extracolonic NCI-sponsored Clinical Extracolonic
Prevention Trials with COX-2 InhibitorsPrevention Trials with COX-2 Inhibitors
InvestigatorInvestigator CohortCohort Agent(s)Agent(s) Primary GoalPrimary Goal PhasePhase
MaoMao Resected Resected lung cancer lung cancer
CelecoxibCelecoxib Dysplasia Dysplasia regressionregression
IIII
KurieKurie Lung Lung dysplasiadysplasia
CelecoxibCelecoxib Biomarker Biomarker modulationmodulation
IIII
FabianFabian Breast Breast cancer riskcancer risk
CelecoxibCelecoxib Biomarker Biomarker modulationmodulation
IIII
KirschKirsch Rectal ACFRectal ACF CelecoxibCelecoxib ACF ACF regression & regression & preventionprevention
IIII
TBDTBD MGUSMGUS CelecoxibCelecoxib Biomarker Biomarker modulationmodulation
IIII
BoyleBoyle Oral Oral leukoplakialeukoplakia
CelecoxibCelecoxib Lesional Lesional regressionregression
IIII
Possible Roles for a Possible Roles for a Chemopreventive Agent in Chemopreventive Agent in
Management of Colorectal NeoplasiaManagement of Colorectal Neoplasia
Possible Roles for a Possible Roles for a Chemopreventive Agent in Chemopreventive Agent in
Management of Colorectal NeoplasiaManagement of Colorectal Neoplasia
• Delay or complement initial Delay or complement initial screeningscreening
• Complement endoscopic Complement endoscopic surveillancesurveillance
– Improve effectivenessImprove effectiveness
• 10-15% polyp miss rate10-15% polyp miss rate
• 5-40% “flat” adenomas5-40% “flat” adenomas
– Reduce procedure-related Reduce procedure-related morbidities and morbidities and inconveniencesinconveniences
• TimeTime
• SedationSedation
• ComplicationsComplications
– Prolong inter-exam intervalsProlong inter-exam intervals
• Delay or complement initial Delay or complement initial screeningscreening
• Complement endoscopic Complement endoscopic surveillancesurveillance
– Improve effectivenessImprove effectiveness
• 10-15% polyp miss rate10-15% polyp miss rate
• 5-40% “flat” adenomas5-40% “flat” adenomas
– Reduce procedure-related Reduce procedure-related morbidities and morbidities and inconveniencesinconveniences
• TimeTime
• SedationSedation
• ComplicationsComplications
– Prolong inter-exam intervalsProlong inter-exam intervals
• Spare or delay primary Spare or delay primary prophylactic polypectomy or prophylactic polypectomy or colectomycolectomy
• Reduce or delay the need for Reduce or delay the need for secondary colorectal secondary colorectal surgeriessurgeries
• Inhibit or retard extracolonic Inhibit or retard extracolonic neoplasianeoplasia
– FAP - duodenal, desmoidsFAP - duodenal, desmoids
– HNPCC - GU, uterine, HNPCC - GU, uterine, upper GIupper GI
– SporadicSporadic
• Inhibit or retard several age-Inhibit or retard several age-related diseasesrelated diseases
• Spare or delay primary Spare or delay primary prophylactic polypectomy or prophylactic polypectomy or colectomycolectomy
• Reduce or delay the need for Reduce or delay the need for secondary colorectal secondary colorectal surgeriessurgeries
• Inhibit or retard extracolonic Inhibit or retard extracolonic neoplasianeoplasia
– FAP - duodenal, desmoidsFAP - duodenal, desmoids
– HNPCC - GU, uterine, HNPCC - GU, uterine, upper GIupper GI
– SporadicSporadic
• Inhibit or retard several age-Inhibit or retard several age-related diseasesrelated diseases
Improve quality of life Improve quality of life Reduce neoplasia incidence & mortalityReduce neoplasia incidence & mortality
Improve quality of life Improve quality of life Reduce neoplasia incidence & mortalityReduce neoplasia incidence & mortality
Tensions to be Considered in Absolute vs. Reasonable Medical Assurance
Tensions to be Considered in Absolute vs. Reasonable Medical Assurance
Scientific Rigor• Accuracy• Reproducibility• Quantitiation• Predictive assurance
Scientific Rigor• Accuracy• Reproducibility• Quantitiation• Predictive assurance
Scientific Practicality• Time• Patients/staff• Finances• Dynamic landscape
Scientific Practicality• Time• Patients/staff• Finances• Dynamic landscape
Once the determinants of disease risk are understood, management of those Once the determinants of disease risk are understood, management of those risks – rather than fulminant disease alone – creates a clinical dilemma risks – rather than fulminant disease alone – creates a clinical dilemma
wherein harm may result from errors of interventional omission or wherein harm may result from errors of interventional omission or comission (i.e., risk itself, may become a “disease” worthy of intervention).comission (i.e., risk itself, may become a “disease” worthy of intervention).
Once the determinants of disease risk are understood, management of those Once the determinants of disease risk are understood, management of those risks – rather than fulminant disease alone – creates a clinical dilemma risks – rather than fulminant disease alone – creates a clinical dilemma
wherein harm may result from errors of interventional omission or wherein harm may result from errors of interventional omission or comission (i.e., risk itself, may become a “disease” worthy of intervention).comission (i.e., risk itself, may become a “disease” worthy of intervention).
Intermediate Endpoints in CV PreventionIntermediate Endpoints in CV Prevention Intermediate Endpoints in CV PreventionIntermediate Endpoints in CV Prevention
““This committee previously recommended, This committee previously recommended, and the Food and Drug Administration and the Food and Drug Administration concurred, that approval of lipid altering concurred, that approval of lipid altering agents should be based on a drug’s agents should be based on a drug’s biochemical efficacy in decreasing serum biochemical efficacy in decreasing serum lipids. Attempts to establish clinical efficacy lipids. Attempts to establish clinical efficacy in the prevention of coronary artery disease in the prevention of coronary artery disease or other manifestations of atherosclerosis, or other manifestations of atherosclerosis, would require prolonged observations and would require prolonged observations and hamper research and development of this hamper research and development of this class of drugs.”class of drugs.”
““This committee previously recommended, This committee previously recommended, and the Food and Drug Administration and the Food and Drug Administration concurred, that approval of lipid altering concurred, that approval of lipid altering agents should be based on a drug’s agents should be based on a drug’s biochemical efficacy in decreasing serum biochemical efficacy in decreasing serum lipids. Attempts to establish clinical efficacy lipids. Attempts to establish clinical efficacy in the prevention of coronary artery disease in the prevention of coronary artery disease or other manifestations of atherosclerosis, or other manifestations of atherosclerosis, would require prolonged observations and would require prolonged observations and hamper research and development of this hamper research and development of this class of drugs.”class of drugs.”
FDA Endocrinologic and Metabolic Drugs Advisory Committee, October 15, 1981FDA Endocrinologic and Metabolic Drugs Advisory Committee, October 15, 1981FDA Endocrinologic and Metabolic Drugs Advisory Committee, October 15, 1981FDA Endocrinologic and Metabolic Drugs Advisory Committee, October 15, 1981
Chemopreventive Drug Development in Chemopreventive Drug Development in Populations at Risk for Colorectal CancerPopulations at Risk for Colorectal CancerChemopreventive Drug Development in Chemopreventive Drug Development in
Populations at Risk for Colorectal CancerPopulations at Risk for Colorectal Cancer
General PopulationGeneral Population: : 40% incidence of adenomas;40% incidence of adenomas;130,000 CRC cases/yr 130,000 CRC cases/yr Lifetime risk ~ 5.6% (2000)Lifetime risk ~ 5.6% (2000)
General PopulationGeneral Population: : 40% incidence of adenomas;40% incidence of adenomas;130,000 CRC cases/yr 130,000 CRC cases/yr Lifetime risk ~ 5.6% (2000)Lifetime risk ~ 5.6% (2000)
Moderate Risk:Moderate Risk:Current/prior adenoma(s), Current/prior adenoma(s), cancer survivor, cancer survivor, Lifetime risk ~ 10-20%Lifetime risk ~ 10-20%
Moderate Risk:Moderate Risk:Current/prior adenoma(s), Current/prior adenoma(s), cancer survivor, cancer survivor, Lifetime risk ~ 10-20%Lifetime risk ~ 10-20%
High RiskHigh Risk:: FAP, HNPCC, IBDFAP, HNPCC, IBDLifetime risk ~ 40-100%Lifetime risk ~ 40-100%
High RiskHigh Risk:: FAP, HNPCC, IBDFAP, HNPCC, IBDLifetime risk ~ 40-100%Lifetime risk ~ 40-100%
CelecoxibCelecoxibNSAID + DFMO (HD)NSAID + DFMO (HD)NSAID + MMPINSAID + MMPINSAID + EGFR inhibitorNSAID + EGFR inhibitor
CelecoxibCelecoxibNSAID + DFMO (HD)NSAID + DFMO (HD)NSAID + MMPINSAID + MMPINSAID + EGFR inhibitorNSAID + EGFR inhibitor
CelecoxibCelecoxib UrsodiolUrsodiolDFMODFMO CalciumCalcium††
MMPIMMPI Folate/B12*Folate/B12*†† EGFR inhibitor EGFR inhibitor SeleniumSeleniumAspirin*Aspirin*††/curcumin/curcumin InulinInulinNSAID + DFMO (LD) NSAID + DFMO (LD)
CelecoxibCelecoxib UrsodiolUrsodiolDFMODFMO CalciumCalcium††
MMPIMMPI Folate/B12*Folate/B12*†† EGFR inhibitor EGFR inhibitor SeleniumSeleniumAspirin*Aspirin*††/curcumin/curcumin InulinInulinNSAID + DFMO (LD) NSAID + DFMO (LD)
CalciumCalcium†† Selenium Selenium Folate/B12*Folate/B12*†† ASA*ASA*††/curcumin/curcuminP. activity*P. activity*†† High F&V/low fat*High F&V/low fat*††
InulinInulin
CalciumCalcium†† Selenium Selenium Folate/B12*Folate/B12*†† ASA*ASA*††/curcumin/curcuminP. activity*P. activity*†† High F&V/low fat*High F&V/low fat*††
InulinInulin
*Active against many cancers†Active against many age-related diseases (e.g., CV, CA, Alzheimer’s)
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AACR Taskforce Working ConclusionAACR Taskforce Working ConclusionAACR Taskforce Working ConclusionAACR Taskforce Working Conclusion
• In CRC risk reduction trials, the adenoma is a In CRC risk reduction trials, the adenoma is a disease endpoint (disease endpoint (i.e.,i.e., a point of clinical intervention a point of clinical intervention and risk)and risk)
– Goal = ~ 30% relative reduction in adenoma Goal = ~ 30% relative reduction in adenoma incidenceincidence
• Other potential clinical benefitsOther potential clinical benefits– Decrease in number of polypectomies and/or procedure-Decrease in number of polypectomies and/or procedure-
related risksrelated risks
– Delay in time to adenomas with malignant potential (Delay in time to adenomas with malignant potential (i.e.,i.e., “advanced” adenomas) “advanced” adenomas)
– Increase intervals between surveillance proceduresIncrease intervals between surveillance procedures
– Organ preservation/delay in time to resection (FAP)Organ preservation/delay in time to resection (FAP)
• In CRC risk reduction trials, the adenoma is a In CRC risk reduction trials, the adenoma is a disease endpoint (disease endpoint (i.e.,i.e., a point of clinical intervention a point of clinical intervention and risk)and risk)
– Goal = ~ 30% relative reduction in adenoma Goal = ~ 30% relative reduction in adenoma incidenceincidence
• Other potential clinical benefitsOther potential clinical benefits– Decrease in number of polypectomies and/or procedure-Decrease in number of polypectomies and/or procedure-
related risksrelated risks
– Delay in time to adenomas with malignant potential (Delay in time to adenomas with malignant potential (i.e.,i.e., “advanced” adenomas) “advanced” adenomas)
– Increase intervals between surveillance proceduresIncrease intervals between surveillance procedures
– Organ preservation/delay in time to resection (FAP)Organ preservation/delay in time to resection (FAP)
O’Shaughnessy JA: Clin Cancer Res 8:314-347, 2002O’Shaughnessy JA: Clin Cancer Res 8:314-347, 2002O’Shaughnessy JA: Clin Cancer Res 8:314-347, 2002O’Shaughnessy JA: Clin Cancer Res 8:314-347, 2002
