1 A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different Methods of Administration of Fluoropyrimidine with Celecoxib versus Placebo as First-line Treatment for Patients with Metastatic Colorectal Cancer Charles Fuchs (Principal Investigator) John Marshall (Co-Principal Investigator) Edith Mitchell (US), Rafal Wierzbicki (Canada), Vinod Ganju (Australia), Mark Jeffery (New Zealand), Joseph Schulz (US), Donald Richards (US), and the BICC-C Study Working Group (>100 study sites) BICC-C Study

2 Background In previous studies of metastatic CRC (mCRC): –Both infusional & bolus regimens of 5-FU with LV and irinotecan confer superior efficacy when compared to 5-FU and LV alone Few studies have compared a combination using infusional 5-FU to the same combination with bolus 5-FU Single-agent capecitabine offers equivalent efficacy to bolus 5-FU and LV in the adjuvant and metastatic setting Few studies have compared combinations using infusional 5-FU & irinotecan to the same combination with capecitabine

3 Background Cyclooxygenase-2 (COX-2) is up regulated in colorectal adenoma and adenocarcinomas In phase III trials, celecoxib reduces the incidence of colorectal adenomas In mouse xenografts of human CRC, celecoxib inhibits angiogenic factors and induces apoptosis and tumor regression In xenografts, celecoxib appears to increase chemotherapy activity and reduce chemotherapy toxicity

4 Original Study Design Celecoxib 400 mg bid 1st-line mCRC N = 1000 Placebo Irinotecan: 180 mg/m 2 (D1) LV: 400 mg/m 2 over 2 h (D1) 5-FU: 400 mg/m 2 (bolus) (D1) 5-FU: 2400 mg/m 2 (46-h infusion) (D1) q2wks FOLFIRI Irinotecan: 125 mg/m 2 (D1, 8) 5-FU: 500 mg/m 2 (bolus) (D1, 8) LV: 20 mg/m 2 (D1, 8) q3wks mIFL Irinotecan: 250 mg/m 2 (D1) Capecitabine: 1000 mg/m 2 bid (D1-14) q3wks CapeIRI RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION Stratification : Age ( 70) PS (0 vs 1) Low dose aspirin use (< 325 mg every day): yes vs no

5 Timeline of Study Events 2002 Period 1 1st Patient Enrolled Feb 2003 Period 2 Add Bevacizumab 1st Patient Enrolled May

6 Period 1: Treatment Regimens Celecoxib 400 mg bid 1st-line mCRC N = 430 2/03–4/04 Placebo Irinotecan: 180 mg/m 2 (D1) LV: 400 mg/m 2 over 2 h (D1) 5-FU: 400 mg/m 2 (bolus) (D1) 5-FU: 2400 mg/m 2 (46-h infusion) (D1) q2wks FOLFIRI Irinotecan: 125 mg/m 2 (D1, 8) 5-FU: 500 mg/m 2 (bolus) (D1, 8) LV: 20 mg/m 2 (D1, 8) q3wks mIFL Irinotecan: 250 mg/m 2 (D1) Capecitabine: 1000 mg/m 2 bid (D1-14) q3wks CapeIRI RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION Stratification : Age ( 70) PS (0 vs 1) Low dose aspirin use (< 325mg every day): yes vs no

7 Period 2: Treatment Regimens Celecoxib 400 mg bid 1st-line mCRC N = 117 5/04–12/04 Placebo Irinotecan: 180 mg/m 2 (D1) LV: 400 mg/m 2 over 2 h (D1) 5-FU: 400 mg/m 2 (bolus) (D1) 5-FU: 2400 mg/m 2 (46-h infusion) (D1) q2wks FOLFIRI Irinotecan: 125 mg/m 2 (D1, 8) 5-FU: 500 mg/m 2 (bolus) (D1, 8) LV: 20 mg/m 2 (D1, 8) q3wks mIFL Irinotecan: 250 mg/m 2 (D1) Capecitabine: 1000 mg/m 2 bid (D1-14) q3wks CapeIRI RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION Stratification: Age, PS, Low dose aspirin use + 5 mg/kg bevacizumab q 2wks mg/kg bevacizumab q 3wks

8 Timeline of Study Events 2002 Period 1 1st Patient Enrolled Feb 2003 Period 2 Add Bevacizumab 1st Patient Enrolled May 2004 Period 2 Enrollment Closed Dec ASCO Abstract Clinical Cut-off: Aug 1, 2005 Database Lock: Dec 20, 2005 ASCO Presentation Clinical Cut-off: Mar 1, 2006 Database Lock: May 10, 2006

9 Eligibility Criteria Metastatic colorectal cancer (mCRC) Measurable disease (RECIST) No prior chemotherapy for mCRC Adjuvant therapy >12 months Age >18 years ECOG Performance Status <1 Adequate hematologic, hepatic, and renal function

10 Study Endpoints Primary endpoint –Progression free survival (PFS) for FOLFIRI vs mIFL Secondary endpoints –PFS, overall survival (OS), response rate, & safety for FOLFIRI vs mIFL vs CapeIRI Celecoxib vs placebo FOLFIRI + bevacizumab vs mIFL + bevacizumab

11 FOLFIRI n =144 mIFL n = 141 CapeIRI n = 145 Median Age (yrs)6162 Male / Female (%)64 / 3659 / 4154 / 46 ECOG PS 0 / 1(%)52 / 4850 / 5048/ 52 Colon (%) Rectum (%) Liver Metastasis (%) Lung Metastasis (%) Number of Organs Involved (%) 1 2 ≥ Prior Adjuvant CT (%)91816 Period 1: Patients Characteristics

12 Period 1: Tumor Response (ITT) Tumor Response FOLFIRI n = 144 (%) mIFL n = 141 (%) CapeIRI n = 145 (%) P value CR PR CR + PR NS SD PD UNK/NE

13 Period 1: Progression Free Survival (ITT)* Clinical Data Cut-Off: August 1 st, Proportion of Progression Free Survival Time (months) FOLFIRI mIFL CapeIRI Regimen Median PFS (Months)HR P Value FOLFIRI8.2-- mIFL (1.1, 1.9) 0.01 CapeIRI (1.1, 1.9) 0.01 *Pre-defined analysis; Data in ASCO 2006 abstract

14 Period 1: Progression Free Survival (ITT) Clinical Data Cut-Off: May 1 st, 2007 Regimen Median PFS (Months) HR (95% CI) P Value FOLFIRI7.8-- mIFL (1.2, 2.0) CapeIRI (1.0, 1.8) Proportion of Subjects Who Did Not Progress FOLFIRI mIFL CapeIRI Time to Progression (months)

15 Period 1: Overall Survival (ITT) Clinical Data Cut-Off: May 1 st, 2007 Survival Time (months) Proportion of Patients Who Survived Regimen Median OS (Months)1 Year HR (95% CI) P Value FOLFIRI23.175%-- mIFL17.665% 1.2 (0.9, 1.6) 0.12 CapeIRI18.966% 1.1 (0.8, 1.4) FOLFIRI mIFL CapeIRI

16 Adverse Event Grade 3-4 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Nausea Vomiting Diarrhea Dehydration Neutropenia Febrile neutropenia Hand-foot syndrome009.9 MI / stroke day mortality Period 1: Common Grade 3-4 Adverse Events

17 FOLFIRI n = 137 n (%) mIFL n = 137 n (%) CapeIRI n = 141 n (%) Progressive disease65 (47.4)75 (54.7)53 (37.6) Unacceptable toxicity12 (8.8)16 (11.7)26 (18.4) > 3 week delay due to toxicity8 (5.8)3 (2.2)10 (7.1) Other anti-cancer treatment7 (5.1) 2 (1.4) Withdraw consent17 (12.4)14 (10.2)15 (10.6) Investigator’s decision23 (16.8)13 (9.5)17 (12.1) Other5 (3.6)9 (6.6)18 (12.7) Period 1: Reasons for Study Discontinuation

18 PERIOD 2 DATA Addition of Bevacizumab Arm A: FOLFIRI + bevacizumab (n = 57) Arm B: mIFL + bevacizumab (n = 60)

19 FOLFIRI + bevacizumab n = 57 mIFL + bevacizumab n = 60 Median Age (yrs)5960 Male / Female (%)53 / 4763 / 37 ECOG PS 0 / 1 / 2 (%)54 / 44 / 253 / 47 / 0 Colon (%) Rectum (%) Liver Metastasis (%) Lung Metastasis (%) No. of Organs Involved (%) 1 2 ≥ Prior Adjuvant CT (%)2313 Period 2: Patients Characteristics

20 Period 2: Progression Free Survival (ITT) Clinical Data Cut-Off: May 1 st, 2007 Proportion of Subjects Who Did Not Progress Regimen Median PFS (Months) HR (95% CI) P Value FOLFIRI + BEV mIFL + BEV (0.8, 2.3) Time to Progression (months) FOLFIRI + Bevacizumab mIFL + Bevacizumab

21 Period 2: Overall Survival (ITT) Clinical Data Cut-Off: May 1 st 2007 Survival Time (months) Regimen Median OS (Months)1 Year HR (95% CI) P Value FOLFIRI+ BEVNot Reached87%-- mIFL + BEV19.261%1.9 (1.2,3.3) 0.01 Proportion of Subjects Who Survived FOLFIRI + Bevacizumab mIFL + Bevacizumab

22 Adverse Event Grade 3-4 FOLFIRI + bevacizumab n = 56 (%) m-IFL + bevacizumab n = 59 (%) Nausea Vomiting Diarrhea Dehydration Neutropenia Febrile neutropenia Hand-foot syndrome Hypertension MI / stroke day mortality Period 2: Common Grade 3-4 Adverse Events

23 Analysis of Celecoxib vs Placebo Period 1 Celecoxib (n = 213) Placebo (n = 217)

24 Celecoxib n = 213 Placebo n = 217 Median Age (yrs)6162 Male / Female (%)60 / 4058 / 42 ECOG PS 0 / 1 (%)50 / 50 Colon (%) Rectum (%) Liver Metastasis (%) Lung Metastasis (%) Number of Organs Involved (%) 1 2 ≥ Prior Adjuvant CT (%)1217 Low dose aspirin use1011 Celecoxib vs Placebo - Period 1: Patients Characteristics

25 Celecoxib vs Placebo - Period 1: PFS (ITT) Clinical Data Cut-Off: May 1 st 2007 Regimen Median PFS (Months) HR (95% CI) P Value Celecoxib6.7-- Placebo (0.8, 1.3) 0.7 Time to Progression (months) Proportion of Subjects Who Did Not Progress Placebo Celecoxib

26 Celecoxib vs Placebo - Period 1: OS (ITT) Clinical Data Cut-Off: May 1 st 2007 Survival Time (months) Proportion of Subjects Who Survived Placebo Celecoxib Regimen Median OS (Months)1 Year HR (95% CI) P Value Celecoxib21.169%-- Placebo18.869%1.1 (0.9, 1.4) 0.49

27 Celecoxib vs Placebo - Period 1: Common Grade 3-4 Adverse Events Adverse Event Celecoxib n = 208 (%) Placebo n = 207 (%) Nausea Vomiting Diarrhea Dehydration Neutropenia Febrile neutropenia Hand-foot syndrome Hypertension MI / stroke day mortality5.32.9

28 Conclusions Period 1 First line FOLFIRI significantly improves PFS when compared with mIFL or CapeIRI Trend in overall survival favors FOLFIRI Toxicity profile generally favors FOLFIRI Period 2 First line FOLFIRI + bevacizumab significantly improves OS compared with mIFL + bevacizumab Both regimens were tolerable Celecoxib Celecoxib neither improved efficacy nor reduced chemotherapy toxicity