Background Document on the UGT1A1 Polymorphisms and Irinotecan Toxicity: ACPS November 3, 2004 Advisory Committee Meeting AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION October 4, 2004 AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

s/Presentations Ando, Proc ASCO 2003 Unspecified Unspecified 119 Japanese genotyped for UGT1A1*28 and UGT1A1 T3263G Not evaluated Severe tox 6.2-fold more likely in pts with both UGT1A1*28 and T3263G than in pts with wild-type UGT1A1 Chowbay, Proc ASCO 2003 100 mg/m, weekly Prospective 20 Chinese pts genotyped; 12 6/6, 6 6/7, and 2 7/7 No significant genotypedependent differences in irino, SN-38, or SN-38G AUC Not evaluated Carlini, Proc ASCO, 2004 Irino, 100-125 mg/m/day, days 1 & 8 every 21 days + capecitabine, 900-1000 mg/m bid, days 2-25 every 21 days Prospective 67 chemonaive metastatic CRC genotyped for UGT1A1*28 as well as UGT1A6 & UGT1A7 polymorphisms Not evaluated No significant associations between UGT1A1 genotypes and toxicity or efficacy. UGT1A7 genotypes conferring lower activity were significantly associated with higher response rate and lack of toxicity. Grem, Proc ASCO 2004 Irino, 70-140 mg/m/24 h + LV, 500 mg/m/30 min + FU 2000-3900 mg/m/48 h, days 1 & 15 every 4 weeks Prospective 30 GI cancer pts genotyped; 9/30 were 6/6 & 21/30 were 6/7 or 7/7 End-of-infusion SN-38G/SN-38 plasma level ratio was lower in 6/6 than in 6/7 or 7/7 genotypes (P=0.037) Not reported Massacesi, Proc ASCO 2004 Irino, 80 mg/m/day, days 1, 8, 15, 22 every 5 weeks + raltitrexed, 3 mg/m, single dose every 3 weeks Prospective 56 pre-treated CRC patients genotyped; genotype frequencies not reported Not evaluated 6/6 protective for diarrhea (P<0.00005), emesis (P<0.0001, and asthenia (P=0.006) Singh, Proc ASCO 2004 Irino, 600 mg fixed dose Prospective 86 adult pts genotyped; 44/86 were 6/6, 37 were 6/7, and 5 were 7/7 Significant genotypedependent trend to SN-38G/SN-38 AUC ratio (P=0.022) Not evaluated