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

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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

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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

Celecoxib400 mg bid

1st-linemCRCN = 1000

Placebo

Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1)5-FU: 400 mg/m2 (bolus) (D1)5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks

FOLFIRI

Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8)LV: 20 mg/m2 (D1, 8) q3wks

mIFL

Irinotecan: 250 mg/m2 (D1)Capecitabine: 1000 mg/m2 bid (D1-14) q3wks

CapeIRI

RANDOMIZATION

RANDOMIZATION

Stratification : Age (< 70 vs > 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 EnrolledMay 2004

2005 2004 2006 2003

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Period 1: Treatment Regimens

Celecoxib400 mg bid

1st-linemCRCN = 4302/03–4/04

Placebo

Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1)5-FU: 400 mg/m2 (bolus) (D1)5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks

FOLFIRI

Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8)LV: 20 mg/m2 (D1, 8) q3wks

mIFL

Irinotecan: 250 mg/m2 (D1)Capecitabine: 1000 mg/m2 bid (D1-14) q3wks

CapeIRI

RANDOMIZATION

RANDOMIZATION

Stratification : Age (< 70 vs > 70) PS (0 vs 1)

Low dose aspirin use (< 325mg every day): yes vs no

7

Period 2: Treatment Regimens

Celecoxib400 mg bid1st-line

mCRCN = 1175/04–12/04

Placebo

Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1)5-FU: 400 mg/m2 (bolus) (D1)5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks

FOLFIRI

Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8)LV: 20 mg/m2 (D1, 8) q3wks

mIFL

Irinotecan: 250 mg/m2 (D1)Capecitabine: 1000 mg/m2 bid (D1-14) q3wks

CapeIRI

RANDOMIZATION

RANDOMIZATION

Stratification: Age, PS, Low dose aspirin use

+ 5 mg/kg bevacizumab q 2wks

+ 7.5 mg/kg bevacizumab q 3wks

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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 2004

2005 2004 2006 2003

ASCO AbstractClinical Cut-off: Aug 1, 2005

Database Lock: Dec 20, 2005

ASCO PresentationClinical Cut-off: Mar 1, 2006Database Lock: May 10, 2006

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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

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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

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FOLFIRIn =144

mIFLn = 141

CapeIRIn = 145

Median Age (yrs) 61 62 62Male / Female (%) 64 / 36 59 / 41 54 / 46ECOG PS 0 / 1(%) 52 / 48 50 / 50 48/ 52Colon (%)Rectum (%)

69 31

65 35

7129

Liver Metastasis (%)Lung Metastasis (%)

8340

7947

8446

Number of Organs Involved (%) 1 2 ≥3

253639

202951

192852

Prior Adjuvant CT (%) 9 18 16

Period 1: Patients Characteristics

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Period 1: Tumor Response (ITT)Tumor

ResponseFOLFIRIn = 144

(%)

mIFLn = 141

(%)

CapeIRIn = 145

(%)

P value

CR 5.6 4.3 2.8 -

PR 41.7 39.0 35.9 -

CR + PR 47.2 43.3 38.6 NS

SD 27.8 36.9 30.3 -

PD 9.0 7.8 11.7 -

UNK/NE 16.0 12.1 19.3 -

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Period 1: Progression Free Survival (ITT)*

Clinical Data Cut-Off: August 1st, 20051.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Prop

ortio

n of

Pr

ogre

ssio

n Fr

ee S

urvi

val

0 10 20 30Time (months)

FOLFIRImIFLCapeIRI

RegimenMedian PFS

(Months) HR P ValueFOLFIRI 8.2 --

mIFL 6.0 1.41(1.1, 1.9)

0.01

CapeIRI 5.7 1.43(1.1, 1.9)

0.01

*Pre-defined analysis; Data in ASCO 2006 abstract

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Period 1: Progression Free Survival (ITT) Clinical Data Cut-Off: May 1st, 2007

RegimenMedian PFS

(Months)HR

(95% CI)P

ValueFOLFIRI 7.8 -- --

mIFL 5.9 1.5(1.2, 2.0)

0.003

CapeIRI 5.8 1.4(1.0, 1.8)

0.012

Prop

ortio

n of

Sub

ject

s W

ho D

id

Not

Pro

gres

s

FOLFIRImIFLCapeIRI

0 10 20 30 40

Time to Progression (months)

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Period 1: Overall Survival (ITT)Clinical Data Cut-Off: May 1st, 2007

Survival Time (months)

Prop

ortio

n of

Pat

ient

sW

ho S

urvi

ved

RegimenMedian OS (Months) 1 Year

HR(95% CI) P Value

FOLFIRI 23.1 75% -- --mIFL 17.6 65% 1.2

(0.9, 1.6) 0.12

CapeIRI 18.9 66% 1.1(0.8, 1.4)

0.42

00.10.20.30.40.50.60.70.80.9

1

0 10 20 30 40 50

FOLFIRImIFLCapeIRI

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Adverse EventGrade 3-4

FOLFIRIn = 137

(%)

m-IFLn = 137

(%)

CapeIRI n = 141

(%)Nausea 8.8 7.3 18.4

Vomiting 8.8 7.3 15.6Diarrhea 13.9 19 47.5Dehydration 5.8 7.3 19.1Neutropenia 43.1 40.9 31.9Febrile neutropenia 3.6 12.4 7.1Hand-foot syndrome 0 0 9.9MI / stroke 0.7 3.6 060-day mortality 3.6 5.1 3.5

Period 1: Common Grade 3-4 Adverse Events

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FOLFIRIn = 137n (%)

mIFLn = 137n (%)

CapeIRIn = 141n (%)

Progressive disease 65 (47.4) 75 (54.7) 53 (37.6)

Unacceptable toxicity 12 (8.8) 16 (11.7) 26 (18.4)

> 3 week delay due to toxicity 8 (5.8) 3 (2.2) 10 (7.1)

Other anti-cancer treatment 7 (5.1) 7 (5.1) 2 (1.4)

Withdraw consent 17 (12.4) 14 (10.2) 15 (10.6) Investigator’s decision 23 (16.8) 13 (9.5) 17 (12.1)

Other 5 (3.6) 9 (6.6) 18 (12.7)

Period 1: Reasons for Study Discontinuation

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PERIOD 2 DATA

Addition of BevacizumabArm A: FOLFIRI + bevacizumab (n = 57)Arm B: mIFL + bevacizumab (n = 60)

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FOLFIRI + bevacizumab

n = 57

mIFL + bevacizumab

n = 60Median Age (yrs) 59 60Male / Female (%) 53 / 47 63 / 37

ECOG PS 0 / 1 / 2 (%) 54 / 44 / 2 53 / 47 / 0Colon (%)Rectum (%)

61 39

70 30

Liver Metastasis (%)Lung Metastasis (%)

8446

8043

No. of Organs Involved (%) 1 2 ≥3

252353

153352

Prior Adjuvant CT (%) 23 13

Period 2: Patients Characteristics

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Period 2: Progression Free Survival (ITT) Clinical Data Cut-Off: May 1st, 2007

Prop

ortio

n of

Sub

ject

s W

ho

Did

Not

Pro

gres

s

RegimenMedian PFS

(Months)HR

(95% CI) P Value

FOLFIRI + BEV 11.2 -- --

mIFL + BEV 8.3 1.4(0.8, 2.3)

0.28

00.10.20.30.40.50.60.70.80.9

1

0 10 20 30Time to Progression (months)

FOLFIRI + Bevacizumab

mIFL + Bevacizumab

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Period 2: Overall Survival (ITT)Clinical Data Cut-Off: May 1st 2007

Survival Time (months)

RegimenMedian OS (Months) 1 Year

HR(95% CI) P Value

FOLFIRI+ BEV Not Reached 87% -- --mIFL + BEV 19.2 61% 1.9

(1.2,3.3)0.01

Prop

ortio

n of

Sub

ject

s W

ho S

urvi

ved

FOLFIRI + Bevacizumab

mIFL + Bevacizumab

00.10.20.30.40.50.60.70.80.9

1

0 10 20 4030

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Adverse EventGrade 3-4

FOLFIRI + bevacizumab

n = 56(%)

m-IFL + bevacizumab

n = 59(%)

Nausea 10.7 5.1Vomiting 10.7 5.1Diarrhea 10.7 11.9Dehydration 5.4 1.7Neutropenia 53.6 28.8Febrile neutropenia 5.4 1.7Hand-foot syndrome 3.6 0.0Hypertension 12.5 1.7MI / stroke 1.8 0.060-day mortality 1.8 6.8

Period 2: Common Grade 3-4 Adverse Events

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Analysis of Celecoxib vs Placebo

Period 1Celecoxib (n = 213)Placebo (n = 217)

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Celecoxibn = 213

Placebon = 217

Median Age (yrs) 61 62Male / Female (%) 60 / 40 58 / 42ECOG PS 0 / 1 (%) 50 / 50 50 / 50Colon (%) Rectum (%)

68.5 31.5

68.2 31.8

Liver Metastasis (%)Lung Metastasis (%)

8548

7941

Number of Organs Involved (%) 1 2 ≥3

222949

213346

Prior Adjuvant CT (%) 12 17Low dose aspirin use 10 11

Celecoxib vs Placebo - Period 1: Patients Characteristics

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Celecoxib vs Placebo - Period 1: PFS (ITT) Clinical Data Cut-Off: May 1st 2007

RegimenMedian PFS

(Months)HR

(95% CI) P Value

Celecoxib 6.7 -- --

Placebo 6. 7 1.0(0.8, 1.3)

0.7

Time to Progression (months)

Prop

ortio

n of

Sub

ject

s W

ho

Did

Not

Pro

gres

s

PlaceboCelecoxib

00.10.20.30.40.50.60.70.80.9

1

0 10 30 4020

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Celecoxib vs Placebo - Period 1: OS (ITT) Clinical Data Cut-Off: May 1st 2007

Survival Time (months)

Prop

ortio

n of

Sub

ject

s W

ho S

urvi

ved

PlaceboCelecoxib

00.10.20.30.40.50.60.70.80.9

1

0 10 30 5020 40

RegimenMedian OS (Months) 1 Year

HR(95% CI) P Value

Celecoxib 21.1 69% -- --Placebo 18.8 69% 1.1

(0.9, 1.4)0.49

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Celecoxib vs Placebo - Period 1:Common Grade 3-4 Adverse Events

AdverseEvent

Celecoxibn = 208

(%)

Placebon = 207

(%)Nausea 12.5 10.6

Vomiting 11.5 9.7Diarrhea 29.8 24.2Dehydration 12.5 9.2Neutropenia 37.0 40.1Febrile neutropenia 8.2 7.2Hand-foot syndrome 4.3 2.4Hypertension 1.4 0.5MI / stroke 1.0 1.960-day mortality 5.3 2.9

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ConclusionsPeriod 1• First line FOLFIRI significantly improves PFS when

compared with mIFL or CapeIRI• Trend in overall survival favors FOLFIRI• Toxicity profile generally favors FOLFIRIPeriod 2• First line FOLFIRI + bevacizumab significantly improves

OS compared with mIFL + bevacizumab• Both regimens were tolerableCelecoxib• Celecoxib neither improved efficacy nor reduced

chemotherapy toxicity