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
Presentation Overview • Commitment to safety • Application of pharmacogenomics at Pfizer • Review & analysis of published data • Ongoing studies • Collaboration with FDA
Pharmacogenomics at Pfizer Discovery Development DISEASE TARGET SELECTING PHARMACO- GENOMICS GENETICS RESPONDERS VARIABILITY Improving Early Decision Making Predicting Efficacy and Safety Choosing the Best Targets Better Understanding of Our Targets .
Chronology of Pharmacogenomics Activities Related to Irinotecan • Ca. 1996-7 - 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 • 2002 - Collaboration with Epidauros AG in PGx of drug transporters and metabolizing enzymes • 2004 - Initiating irinotecan neoadjuvant study with PGx component
Irinotecan Disposition & Metabolism NPC & APC Inactive Metabolites Other UGT Isoforms? CYP3A4/5 Carboxylesterases (CE1 & CE2) UGT1A1 Irinotecan SN-38 SN-38G Active Metabolite Inactive Metabolite Parent Drug GI Absorption Biliary Excretion BCRP MDR1 (PGP)? MRP2? C-MOAT? SN-38 SN-38G Glucuronidase (Bacterial) GI Lumen
Key Publications Correlating UGT1A1 7/7 Genotype and Safety *Full citations given in Background Document.
Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 GenotypesUnadjusted Odds Ratio
Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 GenotypesSummary • 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
Severe (Gr 3+) Diarrhea Risk: 7/7 vs 6/6 + 6/7 GenotypesUnadjusted Odds Ratio • Association between 7/7 and severe diarrhea • 2 of 5 studies show statistical significance
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.
Severe Neutropenia:Translating Associations into a Predictive Test Assumption: Genotyping assay is 100% accurate for detection of UGT1A1*28 allele • Balancing neutropenia and efficacy in 7/7 positive patients: • Neutropenia is generally manageable • Dose reduction may be unnecessary for 50%, with unknown consequences
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
Pfizer-Supported and -Sponsored Trials with a Pharmacogenomic Component* (Nov 2004)
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