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  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 Background

3  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 Background

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 Date: 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 Date: 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 Period 1: Patients Characteristics FOLFIRI n=144 mIFL n=141 CapeIRI n=145 Median Age (yrs)6162 Male / Female (%)64 / 3659 / 4155 / 45 ECOG PS 0 / 1(%)52 / 4850 / 5048/ 52 Colon (%) Rectum (%) Liver Metastasis (%) Lung Metastasis (%) Number of Organs Involved (%) 1 2 ≥ Prior Adjuvant CT (%)91816

12 Period 1: Tumor Response Tumor Response FOLFIRI n=144 (%) mIFL n=141 (%) CapeIRI n=145 (%) P value CR NS PR NS SD NS PD NS UNK/NE5.5 / / / 16.5NS

13 Period 1: Progression Free Survival (ITT)* Clinical Data Cut-Off: 8/01/05 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 Data thru Mar 1, 2006 (ITT) Months Proportion of Progression Free Survival Regimen Median PFS (Months) HR (95% CI) P Value FOLFIRI7.6-- mIFL (1.2, 2.0) CapeIRI (1.1, 1.9) FOLFIRI mIFL CapeIRI

15 Period 1: Multivariate Analysis: PFS Adjusted for Other Prognostic Factors * Includes baseline stratification factors: age, PS, and aspirin use ** Adjusted for age, PS, aspirin use, prior adjuvant therapy, no. of organs involved, and gender FOLFIRI vs mIFLFOLFIRI vs CapeIRI HR (95% CI)* 1.55 (1.2, 2.0) 1.47 (1.1,1.9) Adjusted HR (95% CI)** 1.52 (1.1, 2.0) 1.45 (1.1, 1.9)

16 Period 1: Overall Survival Data thru Mar 1, 2006 (ITT) Survival Time (months) Proportion of Patients Who Survived Regimen Median OS (Months)1 Year HR (95% CI) P Value FOLFIRI23.176%-- mIFL17.665%1.2 (0.9, 1.6) 0.2 CapeIRI18.967%1.2 (0.9, 1.6) 0.17 FOLFIRI mIFL CapeIRI

17 Period 1: Common Grade 3-4 Adverse Events Adverse Event Grade 3-4 FOLFIRI n=137 (%) m-IFL n=137 (%) CapeIRI n=141 (%) Nausea8718 Vomiting7716 Diarrhea Dehydration6719 Neutropenia Febrile neutropenia Hand-foot syndrome0010 MI / stroke day mortality

18 Reasons for Study Discontinuation Period 1 FOLFIRI n = 137 n(%) mIFL n = 137 n(%) CapeIRI n = 141 n(%) Progressive disease64 (46.7)73 (53.3)51 (36.2) Unacceptable toxicity9 (6.6)17 (12.4)24 (17.0) > 3 week delay due to toxicity10 (7.3)2 (1.5)11 (7.8) Other anti-cancer treatment8 (5.8)5 (3.6)3 (2.1) Withdraw consent15 (10.9)14 (10.2)12 (8.5) Investigator’s decision22 (16.1)16 (11.7)14 (9.9) Other9 (6.5)10 (7.3)26 (18.4)

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

20 Period 2: Patients Characteristics FOLFIRI + bevacizumab n=57 mIFL + bevacizumab n=60 Median Age (yrs)5960 Male / Female (%)53 / 4763 / 37 ECOG PS 0 / 1 / 2 (%)54 / 44 / 252 / 48 / 0 Colon (%) Rectum (%) Liver Metastasis (%) Lung Metastasis (%) No. of Organs Involved (%) 1 2 ≥ Prior Adjuvant CT (%)2313

21 Period 2: Progression Free Survival Data thru Mar 1, 2006 (ITT) Months Proportion of Progression Free Survival mIFL + bevacizumab Regimen Median PFS (Months) HR (95% CI) P Value FOLFIRI + BEV9.9-- mIFL + BEV (0.7, 2.0) 0.5 FOLFIRI + bevacizumab

22 Period 2: Overall Survival Data thru Mar 1, 2006 (ITT) Proportion of Patients Who Survived Survival Time (months) Regimen Median OS (Months)1 Year HR (95% CI) P Value FOLFIRI+ BEV Not Reached 87%-- mIFL + BEV18.761%2.5 (1.3,5.0) 0.01 mIFL + bevacizumab FOLFIRI + bevacizumab

23 Period 2: Common Grade 3-4 Adverse Events Adverse Event Grade 3-4 FOLFIRI + bevacizumab n = 56 (%) m-IFL + bevacizumab n = 59 (%) Nausea115 Vomiting115 Diarrhea1112 Dehydration52 Neutropenia5229 Febrile neutropenia Hand-foot syndrome Hypertension MI / stroke day mortality1.86.8

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

25 Celecoxib vs Placebo - Period 1: Patients Characteristics 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 (%)1218 Low dose aspirin use1011

26 Celecoxib vs Placebo - Period 1: PFS thru Mar 1, 2006 (ITT) Months Proportion of Progression Free survival Celecoxib Placebo Regimen Median PFS (Months) HR (95% CI) P Value Celecoxib6.4-- Placebo (0.8, 1.4) 0.7

27 Celecoxib vs Placebo - Period 1: OS thru Mar 1, 2006 (ITT) Survival Time (months) Proportion of Patients Who Survived Regimen Median OS (Months)1 Year HR (95% CI) P Value Celecoxib21.169%-- Placebo18.969%1.0 (0.8, 1.4) 0.8 Celecoxib Placebo

28 Celecoxib vs Placebo - Period 1: Common Grade 3-4 Adverse Events Adverse Event Celecoxib n=208 (%) Placebo n=207 (%) Nausea11 Vomiting1110 Diarrhea2924 Dehydration129 Neutropenia37 Febrile neutropenia Hand-foot syndrome Hypertension MI / stroke day mortality5.32.9

29 Conclusions  First line FOLFIRI significantly improves PFS when compared with mIFL or CapeIRI  Trend in overall survival favors FOLFIRI  Toxicity profile generally favors FOLFIRI Period 1 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

30 Back-Up

31 Treatment Cycles Period 1 FOLFIRI 2-wk cycles m-IFL 3-wk cycles CapeIRI 3-wk cycles Randomized / Treated144 / / / 141 No of cycles received Mean (SE) Median (Range) (0.9) 12 (1 - 48) (0.5) 7 (1 - 31) (0.5) 5 (1 – 35) Treatment duration (days) Mean (SE) Median (Range) (13.1) 184 (15 – 741) (11.8) 168 (22 – 673) (10.7) 114 (22 – 761)

32 Period 1: Death FOLFIRI N=137 n(%) m-IFL N=137 n(%) CapeIRI N=141 n(%) Number of deaths 77 (56.2)87 (63.5)86 (61.0) Cause of death: Cancer Progression Toxicity Other Unknown 72 (52.5) 0(0.0) 2 (1.4) 3 (2.2) 79 (57.7) 2 (1.4) 5 (3.6) 1 (0.7) 80 (56.7) 1 (0.7) 4 (2.8) 1 (0.7)

33 Period 1: Death within 60 days of first cycle FOLFIRI N=137 n(%) m-IFL N=137 n(%) CapeIRI N=141 n(%) Number of deaths 4 (2.9)8 (5.8)5 (3.5) Cause of death: Cancer Progression Toxicity Other Unknown 4 (2.9) 0 (0.0) 6 (4.4) 1 (0.7) 0 (0.0) 2 (1.4) 1 (0.7) 2 (1.4) 0 (0.0)

34 Period 1: Efficacy Results FOLFIRI n = 144 mIFL n = 141 CapeIRI n = 145 Overall RR (%) Median TTP (months) Median OS (months) 1 year survival rate (%)

35 Period 1: Progression Free Survival (Censoring Bevacizumab) (ITT) Months Proportion of Progression Free Survival FOLFIRI mIFL CapeIRI Regimen Median PFS (Months) HR P Value FOLFIRI7.61.0ref mIFL CapeIRI P1 patients did receive bevacizumab after the amendment and were censored for PFS

36 BICC-C: Efficacy Results Excluding Patients Who Discontinued Treatment Within the First 30 Days for Toxicity - Period 1 Period 1Period 2 Without BevacizumabWith Bevacizumab FOLFIRI (n = 144) mIFL (n = 141) CapeIRI (n = 145) FOLFIRI + Avastin (n = 57) mIFL + Avastin (n = 60) PFS (mo) HRNA0.60.7NA1.0 pNA NA0.9

37 Period 1: Second and third line therapy Patients who received n(%) FOLFIRI n=90 mIFL n=91 CapeIRI n=96 Second line chemotherapy87 (96)84 (92)91 (95) Third line chemotherapy28 (31)26 (29)32 (34) Cohort of patients for whom subsequent treatment data are available

38 Period 1: Tumor Response (ITT) Tumor Response FOLFIRI n=116 (%) mIFL n=120 (%) CapeIRI n=112 (%) P value CR9 (7.75)8 (6.6)4 (3.6)NS PR58 (50)51(42.5)51(45.5)NS SD39 (33.6)50 (41.6)42 (37.5)NS PD10 (8.6)11 (9.1)15 (13.4)NS Includes only patients for whom data are available

39 Period 1: Tumor Response (as-treated population)) FOLFIRI N=137 (%) mIFL N=137 (%) CapeIRI N=141 (%) CR PR SD PD UNK/NE

40 Grade 3-4 Hematological Adverse Events Period 1 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Neutropenia Anemia Thrombocytopenia Febrile neutropenia

41 Grade 3-4 Hematological Adverse Events - First 6 weeks Period 1 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Neutropenia Anemia Thrombocytopenia

42 Grade 3-4 Most Common Adverse Events - First 6 weeks Period 1 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Diarrhea Dehydration Abdominal pain/discomfort Nausea Vomiting Stomatitis Hand-Foot Syndrome Myocardial infraction Thrombosis / Embolism3.6 / / / 2.1 Bleeding

43 Grade 3-4 Most Common Adverse Events Period 1 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Diarrhea Dehydration Abdominal pain/discomfort Nausea Vomiting Stomatitis Hand-Foot Syndrome Myocardial infarction Thrombosis/Embolism 13.8 / / / 5.7 Bleeding Cerebrovascular accident / Transient ischaemic attack 0.0 / / / 0.0

44 The Most Common Treatment- Related Clinical Adverse Events (grade 3/4) Period 1 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 145 (%) Diarrhea Abdominal pain/discomfort Nausea Vomiting Stomatitis Asthenia / Fatigue0.7 / / / 9.2 Dehydration Hand-Foot Syndrome Deep Vein Thrombosis

45 Grade 3-4 most common Adverse Events Period 1 FOLFIRI + Avastin N= 56 (%) m-IFL + Avastin N= 59 (%) Diarrhea Dehydration Abdominal pain Nausea Vomiting Stomatitis Hand-Foot Syndrome Hypertension Thrombosis/Embolism 9.0 / / 3.4 Syncope Cerebrovascular accident Proteinuria1.81.7

46 Treatment Cycles Period 2 FOLFIRI + bevacizumab 2-wk cycles m-IFL + bevacizumab 3-wk cycles Randomized / Treated57 / 5660 / 59 No of cycles received Mean (SE) Median (Range) (1.1) 12 (1 - 34) (0.9) 8 (1 - 28) Treatment duration (days) Mean (SE) Median (Range) (17.0) 182 (15 – 540) (18.6) 169 (22 – 589)

47 R easons for study discontinuation Period 2 FOLFIRI + Avastin N= 56 n(%) mIFL + Avastin N= 59 n(%) Progressive disease12 (21.4)18 (30.5) Unacceptable toxicity4 ( 7.1)5 ( 8.5) > 3 week delay due to toxicity3 ( 5.4 )3 ( 5.1) Other anti-cancer treatment3 ( 5.4 )5 ( 8.5) Withdraw consent12 (21.4)14 (23.7) Investigator’s decision11 (19.6) 3 ( 5.1) Other11 (19.7)22 (19.1)

48 Period 2: Second and third line therapy Patients who received n(%) FOLFIRI + bevacizumab n=35 mIFL + bevacizumab n=26 Second line chemotherapy33 (94)19 (73) Third line chemotherapy 5 (14)4 (15) Cohort of patients for which subsequent treatment data is available

49 Death Period 2 FOLFIRI + Avastin N= 56 n(%) m-IFL + Avastin N= 57 n(%) Number of deaths 12 (21.4)25 (42.4) Cause of death: Cancer Progression Toxicity Other Unknown 11 (19.6) 0 (0.0) 1 (1.8) 0 (0.0) 19 (32.2) 1 (1.7) 4 (7.0) 1 (1.7)

50 Grade 3-4 most common Adverse Events -First 6 weeks- Period 2 FOLFIRI + Avastin N= 56 (%) m-IFL + Avastin N= 59 (%) Diarrhea Dehydration Abdominal pain Nausea Vomiting Stomatitis Hypertension Thrombosis / Embolism 1.8 / / 1.7

51 The most common treatment- related clinical adverse events (grade 3/4) Period 2 FOLFIRI + Avastin N= 56 (%) m-IFL + Avastin N= 59 (%) Diarrhea Abdominal pain Nausea Vomiting Stomatitis Asthenia / Fatigue 0.0 / / 5.0 Dehydration Hand-Foot Syndrome Thrombosis / Embolism 5.3 / / 0.0 Hypertension

52 Death within 60 days of first cycle Period 2 FOLFIRI + Avastin N= 56 n(%) m-IFL + Avastin N= 59 n(%) Number of deaths 1 (1.8)4 (6.8) Cause of death: Cancer Progression Toxicity Other 0 (0.0) 1 (1.8) 2 (3.4) 1 (1.7)

53 Tumor Response Rate (ITT) Period 2 FOLFIRI + Avastin N= 57 (%) mIFL + Avastin N= 60 (%) CR3 (5.3)3 (5.0) PR28 (49.1)29 (48.3) SD16 (28.1)16 (26.7) PD5 (8.8)4 (6.7) NE 5 (8.8)8 (13.3)

54 Tumor Response Rate (ITT) Period 2 FOLFIRI + Avastin N=52 (%) mIFL + Avastin N= 52 (%) CR3 (5.3)3 (5.0) PR28 (49.1)29 (48.3) SD16 (28.1)16 (26.7) PD5 (8.8)4 (6.7) Includes only patients for whom data are available

55 Celecoxib vs Placebo - Period1: Tumor Response Tumor Response Celecoxib n= 170 (%) Placebo n= 178 (%) P value CR8(3.8)13(6.0)NS PR75(35.2)85(39.2)NS SD69(32.4)62(28.6)NS PD18(8.5)18(8.3)NS Includes all patients for whom data are available

56 Treatment Cycles Celecoxib vs Placebo - Period 1 CelecoxibPlacebo Randomized / Treated57 / 5660 / 59 No of cycles received Mean (SE) Median (Range) (1.1) 12 (1- 34) (0.9) 8 (1- 28) Treatment duration (days) Mean (SE) Median (Range) (17.0) 182 ( ) (18.6) 169 ( )

57 Reasons for Study Discontinuation Celecoxib vs Placebo - Period 1 Celecoxib n = 208 n(%) Placebo n = 207 n(%) Progressive disease99 (47.6)89 (43) Unacceptable toxicity28 (13.5)22 (10.6) > 3 week delay due to toxicity12 (5.7)11 (5.3) Other anti-cancer treatment8 (3.8) Withdraw consent19 (9.1)22 (10.6) Investigator’s decision26 (12.5) Other16 (7.7)29 (14)

58 Celecoxib vs Placebo - Period1: Tumor Response Tumor Response Celecoxib n= 213 (%) Placebo n= 217 (%) P value CR3.86.0NS PR NS SD NS PD8.58.3NS UNK/NE NS

59 Celecoxib vs Placebo - Period 1: Death Celecoxib n=208 (%) Placebo n=207 (%) Number of deaths125 (60.1)125 (60.4) Cause of death: Cancer Progression Toxicity Other Unknown 117 (93.6) 1 (0.8) 4 (3.2) 3 (2.4) 114 (91.2) 2 (1.6) 7 (5.6) 2 (1.6)

60 Celecoxib vs Placebo - Period 1: Death within 60 days of first dose Celecoxib n=208 (%) Placebo n=207 (%) Number of deaths11 (5.3)6 (2.9) Cause of death: Cancer Progression Toxicity Other 9 (81.8) 1 (9.0) 3 (50.0) 2 (33.3) 1 (16.6)