1 a randomized, multi-center phase iii trial of irinotecan in combination with three different...
DESCRIPTION
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 toxicityTRANSCRIPT
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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
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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
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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
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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