1. Current and Future Perspectives on Irinotecan Pharmacogenomics
ACPS
Clinical Pharmacology Subcommittee
3 November 2004
Luis A. Parodi, PhD - Director and Site Head, Clinical Pharmacogenomics
Mark E. Morrison, MD, PhD - Medical Director, Team Leader, Camptosar
Akintunde Bello, PhD – Associate Director, Clinical Sciences

2. Presentation Overview
Commitment to safety
Application of pharmacogenomics at Pfizer
Review & analysis of published data
Ongoing studies
Collaboration with FDA

3. Pharmacogenomics at Pfizer
Discovery
Development
DISEASE
TARGET
SELECTING
PHARMACO-
GENOMICS
GENETICS
VARIABILITY
RESPONDERS
Improving Early Decision Making
Predicting Efficacy and Safety
Choosing the Best Targets
Better Understanding of Our Targets .

4. Chronology of Pharmacogenomics Activities Related to Irinotecan
Ca Provided irinotecan clinical supplies to NCI in support of early irinotecan pharmacogenomics (PGx) research at University of Chicago
2000 to present - Supported and sponsored several irinotecan clinical trials with PGx
2001 to present - Provided grant support to NCCTG for PGx in N9741 Ph-3 mCRC trial
Collaboration with Epidauros AG in PGx of drug transporters and metabolizing enzymes
Initiating irinotecan neoadjuvant study with PGx component

5. Irinotecan Disposition & Metabolism
NPC & APC
Inactive Metabolites
CYP3A4/5
Carboxylesterases
(CE1 & CE2)
Other UGT Isoforms?
UGT1A1
Irinotecan
SN-38
SN-38G
Parent Drug
Active Metabolite
Inactive
Metabolite
GI Absorption
BCRP
Biliary Excretion
MDR1 (PGP)?
MRP2?
C-MOAT?
SN SN-38G
Glucuronidase
(Bacterial)
GI Lumen

6. Key Publications Correlating UGT1A1 7/7 Genotype and Safety
Author*, Year N
Tumor Type
Irinotecan Dose (mg/m2), Schedule, & Combo
Innocenti, 2004 66
Lung 29%, GE 21%,
CRC 15%, other 35%
350 q-3-wk, single agent
Rouits, 2004 75
CRC 100%
85 wkly + FU/LV
180 biwkly + FU/LV
Marcuello, 2004 95
350 q-3-wk, single agent 350 q-3-wk + raltitrexed
80 wkly + FU
Ando, 2000
118
SCLC 18%,
NSCLC 55%,
CRC 18%, other 9%
Various
Font, 2003 51
NSCLC 100%
70 wkly + docetaxel
*Full citations given in Background Document.

7. Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 Genotypes Unadjusted Odds Ratio
Author
n/N (%)
Est. Odds Ratio
95% CI
7/7
6/6 + 6/7
Innocenti
3/6 (50%)
3/53 (6%)
16.7
Rouits
4/7 (57%)
10/66 (15%)
7.5
Marcuelloa
4/10 (40%)
18/85 (21%)
2.5
Andob
22/111 (20%)
5.4
aGr 3+ neutropenia.
bGr 4 leukopenia and/or Gr 3+ diarrhea.

8. Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 Genotypes Summary
No adjustments for known risk factors
There seems to be a statistically significant association in 3 of 4 studies between 7/7 and severe neutropenia
Potential causes for interstudy variation include:
Small sample sizes
Different schedules/dose intensity
Other known risk factors (bilirubin, age, performance status, pelvic radiation)
Difference in population and cancer types treated

9. Severe (Gr 3+) Diarrhea Risk: 7/7 vs 6/6 + 6/7 Genotypes Unadjusted Odds Ratio
n/N (%)
Est. Odds Ratio
95% CI
7/7
6/6 + 6/7
Innocenti
1/6 (17%)
2/53 (4%)
5.1
Rouits
2/7 (29%)
11/66 (17%)
8.4
Marcuelloa
7/10 (70%)
22/85 (26%)
6.7
Andob
4/7 (57%)
22/111 (20%)
5.4
Font
1/7 (14%)
11/40 (27%)
0.4
aGr 3+ diarrhea; bGr 4 leukopenia and/or Gr 3+ diarrhea.
Association between 7/7 and severe diarrhea
2 of 5 studies show statistical significance

10. Summary of published data
Comprehensive review of published literature
Evaluate the frequencies of severe neutropenia & diarrhea and genotypes
Conclusion:
Significant association of the UGT1A1 7/7 genotype and the risk of developing Grade 4 neutropenia
The association with severe diarrhea not as consistent between studies
Translation of association data to a predictive performance requires assessing multiple parameters
Sensitivity, specificity, and positive & negative predictive values.

11. Severe Neutropenia: Translating Associations into a Predictive Test
Assumption: Genotyping assay is 100% accurate for detection of UGT1A1*28 allele
Clinical Sensitivity
Clinical Specificity
PPV*
NPV*
Innocenti
0.5
0.94
Rouits
0.29
0.95
0.57
0.85
Marcuello
0.18
0.92
0.4
0.79
Ando
0.15
0.97
0.8
Overall
0.22
0.83
* PPV, positive predictive value; NPV, negative predictive value.
Balancing neutropenia and efficacy in 7/7 positive patients:
Neutropenia is generally manageable
Dose reduction may be unnecessary for 50%, with unknown consequences

12. Ongoing Activities
Ongoing Pfizer sponsored and supported trials aim to:
Better quantify the association between the UGT1A1*28 variant (as well as other genetic factors) and severe neutropenia & diarrhea
Discussions are in progress with FDA on revising the Camptosar label to include pharmacogenomics information

13. Pfizer-Supported and -Sponsored Trials with a Pharmacogenomic Component* (Nov 2004)
Protocol
Study Pop’n
Regimens
n***/N
NCCTG N9741
1st-line CRC
IFL, FOLFOX, IROX
520/795
SWOG 0124
Extensive SCLC
cis + irino,
cis + etop
n/620
NCCTG N0147
Stage 3 Adj CRC
FOLFOX  cetux,
FOLFIRI  cetux,
FOLFOX FOLFIRI  cetux
n/4800
PFE BICC-C†**
FOLFIRI + bev  celecox,
IFL + bev  celecox,
(irino + cape  celecox)
>250/1200
PETACC-3†
Stg 2-3 Adj CRC
FU/LV, FU/LV/irino
>700/3278
* Multiple genes tested. ** BICC-C amended to add bev and close irino + cape + celecox arm. *** Number of patients on whom genomic analyses were/will be performed.
† Pfizer-sponsored trial.

14. What do we hope to learn from these studies?
Better define magnitude and strength of the association between UGT1A1*28 and safety
Identify other potential covariates of severe neutropenia & diarrhea
Provide information & guidance to health care practitioners to aid in their treatment decisions