1 A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different...

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 StudyBICC-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

BackgroundBackground

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

BackgroundBackground

4

Original Study DesignOriginal 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

R

A

N

D

O

M

I

Z

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Stratification : Age (< 70 vs > 70)

PS (0 vs 1)

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

5

Timeline of Study EventsTimeline of Study Events

2002

Period 1 1st Patient Enrolled

Date: Feb 2003

Period 2 Add Bevacizumab

1st Patient Enrolled: May 2004

2005 2004 2006 2003

6

Period 1: Treatment RegimensPeriod 1: Treatment Regimens

Celecoxib400 mg bid

1st-linemCRCN = 4302/03–4/04

Placebo


FOLFIRI


mIFL


CapeIRI

R

A

N

D

O

M

I

Z

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Stratification : Age (< 70 vs > 70)

PS (0 vs 1)

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

7

Period 2: Treatment RegimensPeriod 2: Treatment Regimens

Celecoxib400 mg bid1st-line

mCRCN = 1175/04–12/04

Placebo


FOLFIRI


mIFL


CapeIRI

R

A

N

D

O

M

I

Z

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Stratification: Age, PS, Low dose aspirin use

+ 5 mg/kg bevacizumab q 2wks

+ 7.5 mg/kg bevacizumab q 3wks

8

Timeline of Study EventsTimeline 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 2004

2005 2004 2006 2003

ASCO AbstractClinical Cut-off: Aug 1, 2005

Database Lock: Dec 20, 2005

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

9

Eligibility CriteriaEligibility 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 EndpointsStudy 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 CharacteristicsPeriod 1: Patients Characteristics

FOLFIRI

n=144

mIFL

n=141

CapeIRI

n=145

Median Age (yrs) 61 62 62

Male / Female (%) 64 / 36 59 / 41 55 / 45

ECOG PS 0 / 1(%) 52 / 48 50 / 50 48/ 52

Colon (%)Rectum (%)

72 28

71 29

7624

Liver Metastasis (%)Lung Metastasis (%)

8340

7947

8546

Number of Organs Involved (%) 1 2 ≥3

253639

202951

192852

Prior Adjuvant CT (%) 9 18 16

12

Period 1: Tumor Response Period 1: Tumor Response

TumorResponse

FOLFIRIn=144

(%)

mIFLn=141

(%)

CapeIRIn=145

(%)

P value

CR 6.3 5.7 2.8 NS

PR 40.3 36.2 35.2 NS

SD 27.1 35.5 29.0 NS

PD 6.9 7.8 10.3 NS

UNK/NE 5.5 / 14.6 4.2 / 10.6 6.2 / 16.5 NS

13

Period 1: Progression Free Survival (ITT)* Clinical Data Cut-Off: 8/01/05Period 1: Progression Free Survival (ITT)* Clinical Data Cut-Off: 8/01/05

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

po

rtio

n o

f P

rog

ress

ion

Fre

e S

urv

ival

0 10 20 30

Time (months)

FOLFIRI

mIFL

CapeIRI

RegimenMedian PFS

(Months) HR P Value

FOLFIRI 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

14

00.10.20.30.40.50.60.70.80.9

1

0 5 10 15 20 25 30

Period 1: Progression Free Survival Data thru Mar 1, 2006 (ITT)Period 1: Progression Free Survival Data thru Mar 1, 2006 (ITT)

Months

Pro

po

rtio

n o

f P

rog

ress

ion

Fre

e S

urv

ival

RegimenMedian PFS

(Months)HR

(95% CI)P

Value

FOLFIRI 7.6 -- --

mIFL 5.8 1.55(1.2, 2.0)

0.0009

CapeIRI 5.5 1.47(1.1, 1.9)

0.0049

FOLFIRI

mIFL

CapeIRI

15

Period 1: Multivariate Analysis: PFS Adjusted for Other Prognostic Factors

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 mIFL FOLFIRI 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

00.10.20.30.40.50.60.70.80.9

1

0 5 10 15 20 25 30 35 40

Period 1: Overall Survival Data thru Mar 1, 2006 (ITT) Period 1: Overall Survival Data thru Mar 1, 2006 (ITT)

Survival Time (months)

Pro

po

rtio

n o

f P

atie

nts

Wh

o S

urv

ived

RegimenMedian OS (Months) 1 Year

HR(95% CI) P Value

FOLFIRI 23.1 76% -- --

mIFL 17.6 65% 1.2(0.9, 1.6)

0.2

CapeIRI 18.9 67% 1.2(0.9, 1.6)

0.17

FOLFIRI

mIFL

CapeIRI

17

Period 1: Common Grade 3-4 Adverse EventsPeriod 1: Common Grade 3-4 Adverse Events

Adverse EventGrade 3-4

FOLFIRIn=137

(%)

m-IFLn=137

(%)

CapeIRI n=141

(%)

Nausea 8 7 18

Vomiting 7 7 16

Diarrhea 13 19 48

Dehydration 6 7 19

Neutropenia 40 39 31

Febrile neutropenia 2.2 6.6 5.0

Hand-foot syndrome 0 0 10

MI / stroke 0.7 4.4 0

60-day mortality 2.9 5.8 3.5

18

Reasons for Study Discontinuation Period 1Reasons for Study Discontinuation Period 1

FOLFIRI

n = 137n(%)

mIFL

n = 137n(%)

CapeIRI

n = 141n(%)

Progressive disease 64 (46.7) 73 (53.3) 51 (36.2)

Unacceptable toxicity 9 (6.6) 17 (12.4) 24 (17.0)

> 3 week delay due to toxicity 10 (7.3) 2 (1.5) 11 (7.8)

Other anti-cancer treatment 8 (5.8) 5 (3.6) 3 (2.1)

Withdraw consent 15 (10.9) 14 (10.2) 12 (8.5)

Investigator’s decision 22 (16.1) 16 (11.7) 14 (9.9)

Other 9 (6.5) 10 (7.3) 26 (18.4)

19

PERIOD 2 DATAPERIOD 2 DATA

Addition of BevacizumabAddition 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 CharacteristicsPeriod 2: Patients Characteristics

FOLFIRI + bevacizumab

n=57

mIFL + bevacizumab

n=60

Median Age (yrs) 59 60

Male / Female (%) 53 / 47 63 / 37

ECOG PS 0 / 1 / 2 (%) 54 / 44 / 2 52 / 48 / 0

Colon (%)Rectum (%)

61 39

68 32


8444

8043

No. of Organs Involved (%) 1 2 ≥3

252353

153352

Prior Adjuvant CT (%) 23 13

21

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20

Period 2: Progression Free Survival Data thru Mar 1, 2006 (ITT) Period 2: Progression Free Survival Data thru Mar 1, 2006 (ITT)

Months

Pro

po

rtio

n o

f P

rog

ress

ion

Fre

eS

urv

ival

mIFL + bevacizumab

RegimenMedian PFS

(Months)HR

(95% CI) P Value

FOLFIRI + BEV 9.9 -- --

mIFL + BEV 8.3 1.1(0.7, 2.0)

0.5


22

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30

Period 2: Overall Survival Data thru Mar 1, 2006 (ITT) Period 2: Overall Survival Data thru Mar 1, 2006 (ITT)

Pro

po

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n o

f P

atie

nts

Wh

o S

urv

ived


Regimen

Median OS

(Months) 1 YearHR

(95% CI) P Value

FOLFIRI+ BEV Not Reached 87% -- --

mIFL + BEV 18.7 61% 2.5(1.3,5.0)

0.01

mIFL + bevacizumab


23

Period 2: Common Grade 3-4 Adverse EventsPeriod 2: Common Grade 3-4 Adverse Events

Adverse EventGrade 3-4

FOLFIRI + bevacizumabn = 56

(%)

m-IFL + bevacizumabn = 59

(%)

Nausea 11 5

Vomiting 11 5

Diarrhea 11 12

Dehydration 5 2

Neutropenia 52 29

Febrile neutropenia 3.6 1.7

Hand-foot syndrome 3.6 0.0

Hypertension 12.5 1.7

MI / stroke 1.8 0.0

60-day mortality 1.8 6.8

24

Analysis of Celecoxib vs Placebo

Analysis of Celecoxib vs Placebo

Period 1Period 1

Celecoxib (n = 213)

Placebo (n = 217)

Celecoxib (n = 213)

Placebo (n = 217)

25

Celecoxib vs Placebo - Period 1: Patients CharacteristicsCelecoxib vs Placebo - Period 1: Patients Characteristics

Celecoxibn = 213

Placebon = 217

Median Age (yrs) 61 62

Male / Female (%) 60 / 40 58 / 42

ECOG PS 0 / 1 (%) 50 / 50 50 / 50

Colon (%) Rectum (%)

71 29

74 26


8548

7941

Number of Organs Involved (%) 1 2 ≥3

222949

213346

Prior Adjuvant CT (%) 12 18

Low dose aspirin use 10 11

26

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30

Celecoxib vs Placebo - Period 1: PFS thru Mar 1, 2006 (ITT) Celecoxib vs Placebo - Period 1: PFS thru Mar 1, 2006 (ITT)

Months

Pro

po

rtio

n o

f P

rog

ress

ion

F

ree

surv

ival

Celecoxib

Placebo

Regimen

Median PFS

(Months)HR

(95% CI) P Value

Celecoxib 6.4 -- --

Placebo 6.5 0.96 (0.8, 1.4)

0.7

27

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30 35 40

Celecoxib vs Placebo - Period 1: OS thru Mar 1, 2006 (ITT)Celecoxib vs Placebo - Period 1: OS thru Mar 1, 2006 (ITT)


Pro

po

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f P

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nts

Wh

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urv

ived

RegimenMedian OS (Months) 1 Year

HR(95% CI) P Value

Celecoxib 21.1 69% -- --

Placebo 18.9 69% 1.0

(0.8, 1.4)

0.8

Celecoxib

Placebo

28

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

AdverseEvent

Celecoxibn=208

(%)

Placebon=207

(%)

Nausea 11 11

Vomiting 11 10

Diarrhea 29 24

Dehydration 12 9

Neutropenia 37 37

Febrile neutropenia 4.8 4.3

Hand-foot syndrome 4.3 2.4


MI / stroke 1.4 1.9

60-day mortality 5.3 2.9

29

ConclusionsConclusions

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-UpBack-Up

31

Treatment CyclesPeriod 1Treatment CyclesPeriod 1

FOLFIRI

2-wk cycles

m-IFL

3-wk cycles

CapeIRI

3-wk cycles

Randomized / Treated 144 / 137 141/ 137 145 / 141

No of cycles received

Mean (SE)

Median (Range)

1881

13.7 (0.9)

12 (1 - 48)

1095

8.0 (0.5)

7 (1 - 31)

878

6.2 (0.5)

5 (1 – 35)

Treatment duration (days)

Mean (SE)

Median (Range)

211.4 (13.1)

184 (15 – 741)

179.8 (11.8)

168 (22 – 673)

142.9 (10.7)

114 (22 – 761)

32

Period 1: DeathPeriod 1: Death

FOLFIRI N=137n(%)

m-IFLN=137 n(%)

CapeIRI N=141n(%)

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 Period 1: Death within 60 days of first cycle

FOLFIRI N=137n(%)

m-IFLN=137 n(%)

CapeIRI N=141n(%)

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)

0 (0.0)

0 (0.0)

6 (4.4)

1 (0.7)

1 (0.7)

0 (0.0)

2 (1.4)

1 (0.7)

2 (1.4)

0 (0.0)

34

Period 1: Efficacy ResultsPeriod 1: Efficacy Results

FOLFIRI

n = 144mIFL

n = 141CapeIRI

n = 145

Overall RR (%)

Median TTP (months) 8.11 5.65 5.95

Median OS (months)

1 year survival rate (%)

35

00.10.20.30.40.50.60.70.80.9

1

0 5 10 15 20 25 30

Period 1: Progression Free Survival(Censoring Bevacizumab) (ITT)Period 1: Progression Free Survival(Censoring Bevacizumab) (ITT)

Months

Pro

po

rtio

n o

f P

rog

ress

ion

Fre

e S

urv

ival

FOLFIRI mIFL CapeIRI

RegimenMedian PFS

(Months)HR

P Value

FOLFIRI 7.6 1.0 ref

mIFL 5.8 0.66 0.003

CapeIRI 5.5 0.70 0.012

23 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

BICC-C: Efficacy Results Excluding Patients Who Discontinued Treatment Within the First 30 Days for Toxicity - Period 1

Period 1 Period 2

Without Bevacizumab With Bevacizumab

FOLFIRI

(n = 144)

mIFL

(n = 141)

CapeIRI

(n = 145)

FOLFIRI +

Avastin

(n = 57)

mIFL +

Avastin

(n = 60)

PFS (mo) 8.11 5.65 5.95 9.92 9.63

HR NA 0.6 0.7 NA 1.0

p NA 0.0005 0.015 NA 0.9

37

Period 1: Second and third line therapyPeriod 1: Second and third line therapy

Patients who received n(%)FOLFIRI

n=90mIFLn=91

CapeIRI

n=96

Second line chemotherapy 87 (96) 84 (92) 91 (95)

Third line chemotherapy 28 (31) 26 (29) 32 (34)

Cohort of patients for whom subsequent treatment data are available

38

Period 1: Tumor Response (ITT) Period 1: Tumor Response (ITT)

TumorResponse

FOLFIRIn=116

(%)

mIFLn=120

(%)

CapeIRIn=112

(%)

P value

CR 9 (7.75) 8 (6.6) 4 (3.6) NS

PR 58 (50) 51(42.5) 51(45.5) NS

SD 39 (33.6) 50 (41.6) 42 (37.5) NS

PD 10 (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)) Period 1: Tumor Response (as-treated population))

FOLFIRI

N=137(%)

mIFL

N=137(%)

CapeIRI

N=141(%)

CR 6.6 5.8 2.8

PR 42.3 37.2 36.2

SD 28.5 36.5 29.8

PD 7.3 8.0 10.6

UNK/NE 15.3 12.4 20.6

40

Grade 3-4 Hematological Adverse Events Period 1

Grade 3-4 Hematological Adverse Events Period 1

FOLFIRI n = 137

(%)

m-IFLn = 137

(%)

CapeIRI n = 141

(%)

Neutropenia 40.1 39.4 31.9

Anemia 4.4 2.9 4.3

Thrombocytopenia 0.7 0.0 0.7

Febrile neutropenia 4.3 8.7 6.3

41

Grade 3-4 Hematological Adverse Events - First 6 weeksPeriod 1

Grade 3-4 Hematological Adverse Events - First 6 weeksPeriod 1

FOLFIRI n = 137

(%)

m-IFL n = 137

(%)

CapeIRI n = 141

(%)

Neutropenia 15.3 27.0 17.0

Anemia 2.2 1.5 3.5

Thrombocytopenia 0.0 0.0 0.7

42

Grade 3-4 Most Common Adverse Events - First 6 weeksPeriod 1

Grade 3-4 Most Common Adverse Events - First 6 weeksPeriod 1

FOLFIRI n = 137

(%)

m-IFL n = 137

(%)

CapeIRI n = 141

(%)

Diarrhea 5.1 14.6 33.3

Dehydration 3.6 5.8 13.5

Abdominal pain/discomfort 5.1 1.5 7.8

Nausea 3.6 4.4 16.3

Vomiting 4.4 2.9 14.9

Stomatitis 0.0 0.0 2.8

Hand-Foot Syndrome 0.0 0.0 4.3

Myocardial infraction 0.7 2.2 0.0

Thrombosis / Embolism 3.6 / 0.0 0.7 / 0.7 2.8 / 2.1

Bleeding 0.0 0.7 1.4

43

Grade 3-4 Most Common Adverse EventsPeriod 1

Grade 3-4 Most Common Adverse EventsPeriod 1

FOLFIRIn = 137

(%)

m-IFLn = 137

(%)

CapeIRI n = 141

(%)

Diarrhea 13.1 19.0 47.5



Nausea 8.0 6.6 17.7

Vomiting 7.3 7.3 15.6



Myocardial infarction 0.7 2.9 0.0

Thrombosis/Embolism 13.8 / 2.2 9.4 / 6.6 8.5 / 5.7

Bleeding 0.7 1.5 1.4

Cerebrovascular accident / Transient ischaemic attack

0.0 / 0.7 1.5 / 0.7 0.0 / 0.0

44

The Most Common Treatment-Related Clinical Adverse Events (grade 3/4) Period 1

The Most Common Treatment-Related Clinical Adverse Events (grade 3/4) Period 1

FOLFIRI n = 137

(%)

m-IFL n = 137

(%)

CapeIRI n = 145

(%)

Diarrhea 10.2 14.5 43.9


Nausea 2.9 10.4 14.8

Vomiting 2.1 5.8 13.4


Asthenia / Fatigue 0.7 / 8.0 3.6 / 8.0 4.2 / 9.2



Deep Vein Thrombosis 1.4 1.4 2.1

45

Grade 3-4 most common Adverse Events Period 1 Grade 3-4 most common Adverse Events Period 1

FOLFIRI + AvastinN= 56

(%)

m-IFL + AvastinN= 59

(%)

Diarrhea 10.7 11.9

Dehydration 5.4 1.7

Abdominal pain 8.9 8.5

Nausea 10.7 5.1

Vomiting 10.7 5.1

Stomatitis 3.6 0.0

Hand-Foot Syndrome 3.6 0.0


Thrombosis/Embolism 9.0 /7.2 5.1 / 3.4

Syncope 3.6 1.7

Cerebrovascular accident

1.8 0.0

Proteinuria 1.8 1.7

46

Treatment CyclesPeriod 2Treatment CyclesPeriod 2


2-wk cycles

m-IFL + bevacizumab

3-wk cycles

Randomized / Treated 57 / 56 60 / 59


Mean (SE)

Median (Range)

672

12.0 (1.1)

12 (1 - 34)

485

8.2 (0.9)

8 (1 - 28)


Mean (SE)

Median (Range)

187.8 (17.0)

182 (15 – 540)

183.0 (18.6)

169 (22 – 589)

47

Reasons for study discontinuation Period 2Reasons for study discontinuation Period 2

FOLFIRI + Avastin

N= 56n(%)

mIFL + Avastin

N= 59n(%)

Progressive disease 12 (21.4) 18 (30.5)

Unacceptable toxicity 4 ( 7.1) 5 ( 8.5)

> 3 week delay due to toxicity 3 ( 5.4 ) 3 ( 5.1)

Other anti-cancer treatment 3 ( 5.4 ) 5 ( 8.5)

Withdraw consent 12 (21.4) 14 (23.7)

Investigator’s decision 11 (19.6)3 ( 5.1)

Other 11 (19.7) 22 (19.1)

48

Period 2: Second and third line therapyPeriod 2: Second and third line therapy

Patients who received n(%)


n=35

mIFL + bevacizumab

n=26

Second line chemotherapy 33 (94) 19 (73)

Third line chemotherapy 5 (14) 4 (15)

Cohort of patients for which subsequent treatment data is available

49

Death Period 2Death Period 2

FOLFIRI + AvastinN= 56n(%)

m-IFL + AvastinN= 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

Grade 3-4 most common Adverse Events -First 6 weeks- Period 2


(%)


(%)

Diarrhea 1.8 6.8

Dehydration 1.8 0.0


Nausea 3.6 5.1

Vomiting 5.4 5.1

Stomatitis 1.8 0.0


Thrombosis / Embolism 1.8 / 0.0 0.0 / 1.7

51

The most common treatment-related clinical adverse events(grade 3/4) Period 2

The most common treatment-related clinical adverse events(grade 3/4) Period 2


(%)


(%)

Diarrhea 5.3 11.8


Nausea 7.1 3.3

Vomiting 7.1 3.3

Stomatitis 1.7 0.0

Asthenia / Fatigue 0.0 / 8.9 1.6 / 5.0

Dehydration 3.5 1.6

Hand-Foot Syndrome 3.5 0.0

Thrombosis / Embolism 5.3 / 1.7 0.0 / 0.0


52

Death within 60 days of first cycle Period 2Death within 60 days of first cycle Period 2

FOLFIRI + AvastinN= 56 n(%)

m-IFL + AvastinN= 59 n(%)

Number of deaths 1 (1.8) 4 (6.8)

Cause of death:

Cancer Progression

Toxicity

Other

0 (0.0)

0 (0.0)

1 (1.8)

2 (3.4)

1 (1.7)

1 (1.7)

53

Tumor Response Rate (ITT)Period 2Tumor Response Rate (ITT)Period 2

FOLFIRI + Avastin

N= 57(%)

mIFL + Avastin

N= 60(%)

CR 3 (5.3) 3 (5.0)

PR 28 (49.1) 29 (48.3)

SD 16 (28.1) 16 (26.7)

PD 5 (8.8) 4 (6.7)

NE5 (8.8) 8 (13.3)

54

Tumor Response Rate (ITT)Period 2Tumor Response Rate (ITT)Period 2

FOLFIRI + Avastin

N=52(%)

mIFL + Avastin

N= 52(%)

CR 3 (5.3) 3 (5.0)

PR 28 (49.1) 29 (48.3)

SD 16 (28.1) 16 (26.7)

PD 5 (8.8) 4 (6.7)

Includes only patients for whom data are available

55

Celecoxib vs Placebo - Period1: Tumor ResponseCelecoxib vs Placebo - Period1: Tumor Response

TumorResponse

Celecoxibn= 170

(%)

Placebon= 178

(%)

P value

CR 8(3.8) 13(6.0) NS

PR 75(35.2) 85(39.2) NS

SD 69(32.4) 62(28.6) NS

PD 18(8.5) 18(8.3) NS

Includes all patients for whom data are available

56

Treatment CyclesCelecoxib vs Placebo - Period 1Treatment CyclesCelecoxib vs Placebo - Period 1

Celecoxib Placebo

Randomized / Treated 57 / 56 60 / 59


Mean (SE)

Median (Range)

672

12.0 (1.1)

12 (1- 34)

485

8.2 (0.9)

8 (1- 28)


Mean (SE)

Median (Range)

187.8 (17.0)

182 (15- 540)

183.0 (18.6)

169 (22- 589)

57

Reasons for Study Discontinuation Celecoxib vs Placebo - Period 1Reasons for Study Discontinuation Celecoxib vs Placebo - Period 1

Celecoxib

n = 208n(%)

Placebo

n = 207n(%)

Progressive disease 99 (47.6) 89 (43)

Unacceptable toxicity 28 (13.5) 22 (10.6)

> 3 week delay due to toxicity 12 (5.7) 11 (5.3)

Other anti-cancer treatment 8 (3.8) 8 (3.8)

Withdraw consent 19 (9.1) 22 (10.6)

Investigator’s decision 26 (12.5) 26 (12.5)

Other 16 (7.7) 29 (14)

58

Celecoxib vs Placebo - Period1: Tumor ResponseCelecoxib vs Placebo - Period1: Tumor Response

TumorResponse

Celecoxibn= 213

(%)

Placebon= 217

(%)

P value

CR 3.8 6.0 NS

PR 35.2 39.2 NS

SD 32.4 28.6 NS

PD 8.5 8.3 NS

UNK/NE 20.2 18.0 NS

59

Celecoxib vs Placebo - Period 1:Death Celecoxib vs Placebo - Period 1:Death

Celecoxibn=208

(%)

Placebon=207

(%)

Number of deaths 125 (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 doseCelecoxib vs Placebo - Period 1:Death within 60 days of first dose

Celecoxibn=208

(%)

Placebon=207

(%)

Number of deaths 11 (5.3) 6 (2.9)

Cause of death:

Cancer Progression

Toxicity

Other

9 (81.8)

1 (9.0)

1 (9.0)

3 (50.0)

2 (33.3)

1 (16.6)

Date post:	13-Jan-2016
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