sNDA 20-571

“Irinotecan as a component of first line treatment of patients with

metastatic colorectal cancer.”

APPROVED SCHEDULES (SINGLE AGENT)

• 125 mg/m2 wkly x 4 Q6 wks

• 350 mg/m2 Q3 wks

PROPOSED SCHEDULES(CPT-11 + 5FU/LV)

CPT-11+ BOLUS CPT-11 + 5FU/LV weekly x 4 (Saltz)

less dose intense “Roswell Park”

CPT-11+ CONTINUOUS INFUSION CPT-11 + biweekly CIV (deGramont) CPT-11 + weekly CIV (AIO)

STUDY DESIGN0038 (U.S.)

ARM A : CPT-11 125 wk x 4 Q 6 wks (n=226)

ARM B : CPT-11 125 wk x 4 Q 6 wks(n=231) 5FU 500 bolus LV 20

ARM C : 5FU 425 daily x 5(n=226) LV 20

STUDY DESIGNv303 (EUROPE)

ARM A(n=198)

CPT-11+5FU/LV

ARM B(n=187)

5FU/LV

A1(n=54)

A2(n=145)

B1(n=43)

B2(n=143)

CPT-11+ wkly CIV

(AIO)

CPT-11+ biwkly CIV(deGramont)

AIO deGramont

EFFICACY ENDPOINTS(U.S.)

ARM A: CPT-11 ARM B:: CPT-11 ARM C: 5FU 5FU LV LV

10 : TIME TO TUMOR PROGRESSION

2o : SURVIVAL

STUDY DESIGN(Europe)

10: RESPONSE RATE

20: SURVIVAL

TTP

ARM A

CPT-11+5FU/LV

ARM B

5FU/LV

A1 A2 B1 B2

CPT-11+ weekly CIV

5FU/LV(AIO)

CPT-11+ biweekly CIV

5FU/LV(deGramont)

Wkly CIV5FU/LV

(AIO)

Biweekly CIV5FU/LV

(deGramont)

DATA ANALYSIS

• Survival

• Key safety parameters

• Supportiveness of other efficacy endpoints

INCLUSION CRITERIA

STUDY 0038 (U.S.) STUDY V303 (EUROPE)

>18 18-75

ECOG</=2 WHO </= 2

Good Organ Function Good Organ Function

No Prior Radiation Prior Radiation Allowed

Adjuvant > 12 months Adjuvant > 6 months

PATIENT DEMOGRAPHICS(U.S. and Europe)

• Well balanced

• More Rectal Cancer: Europe

DEATHS(Europe)

40

51

64

73

0

20

40

60

80

100

Feb 1999 Oct 1999

CPT-11+5FU/LV 5FU/LV

• Enrollment: May 97 to Feb 98

• Cut-off: Feb 99 Oct 99%

DE

AT

HS

SURVIVAL v303 (Europe)

MEDIAN SURVIVAL (Months)

February 1999

A (CPT-11+5FU/LV = 16.8B (5FU/LV) = 14

October 1999

A (CPT-11+5FU/LV = 17.4B (5FU/LV) =14.1

p = 0.028

p = 0.032

Months

Pro

ba

bili

ty

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1.0

Euro. Study, IIT Pop. KM survivalestimates

Irinotecan/5FU/LV5FU/LV

DEATHS(U.S.)

67

7873

82

0

20

40

60

80

100

Sept 99 Dec 99

CPT-11+5FU/LV 5-FU/LV

• Enrollment: May 96 to May 98

• Cut-off: Sept 99 Dec 99

% D

EA

TH

S

SURVIVAL 0038 (U.S.)

MEDIAN SURVIVAL (Months)

September 1999

B 14.5C 12.6

A

December 1999

B 14.8C 12.6

A 12.0

p = 0.097

p = 0.042HR = 0.81

0 1 0 2 0 3 0 4 0

M o n th s

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

U S S tu d y IT T P o p u la tio n K M s u rv iv a l e s tim a te s

p = 0 .0 4 2

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

C P T -1 1C P T -1 1 + 5 F U /L V5 F U /L V

CROSS OVER TO CPT-11

U.S.

B CPT-11+5FU/LV

C 5FU/LV 40% CPT-11

A CPT-11

EUROPE

A CPT-11+5FU/LV

B 5FU/LV 30% CPT-11

TIME TO TUMOR PROGRESSION

(Months)

EUROPE U.S.

CPT-11+ CIV 5FU/LV

(N=198)

5FU/LV

(N=187)

CPT-11+ weekly5FU/LV

(N=231)

5FU/LV

(N=226)

CPT-11

(N=226)

6.7 4.4 7.0 4.3 4.2

p < 0.001 p < 0.004

TIME TOTREATMENT FAILURE

(Months)

EUROPE U.S.

CPT-11+ CIV 5FU/LV

(N=198)

5FU/LV

(N=187)

CPT-11+ weekly5FU/LV

(N=231)

5FU/LV

(N=226)

CPT-11

(N=226)

5.3 3.8 5.4 3.7 3.2

p < 0.0014 p < 0.001

RESPONSE RATE

EUROPE U.S.

CPT-11+ CIV 5FU/LV

(N=198)

5FU/LV

(N=187)

CPT-11+ weekly5FU/LV

(N=231)

5FU/LV

(N=226)

CPT-11

(N=226)

35% 22% 39% 21% 18%

p < 0.005 p < 0.001

SUMMARY OF EFFICACY

STRENGTHS

• Consistent survival advantage (Europe)

• Survival advantage in ff-up analysis (US)

• Significant differences in TTP, TTF and response rate

CONCERNS

• Which CIV schedule offers “real” advantage (Europe)

– CPT-11+ biweekly?

– CPT-11+ weekly?

# of Patients

ARM A (CPT-11+5FU/LV)

A1 CPT-11 + weekly CIV 53

A2 CPT-11 + biweekly CIV 145

ARM B (5FU/LV)

B1 weekly CIV 44

B2 biweekly CIV 143

ACCRUAL: TREATMENT SUBGROUPS

(EUROPE)

EFFICACY: TREATMENT SUBGROUPS

(EUROPE)

CPT-11+weekly

CIV

(N=54)

WeeklyCIV

(N=43)

CPT-11+biweekly

CIV

(N=145)

BiweeklyCIV

(N=143)

19.2 14.1 15.6 13.0MedianSurvival(Months)

p = 0.48 p = 0.04

7.2 6.5 6.5 3.7Median

TTP(Months)

p = 0.18 p = 0.001

40% 25% 33% 21%ResponseRate

p = 0.13 p = 0.02

SAFETY REVIEW

• Europe CPT-11+wkly CPT-11+ biweekly

• U.S.

GRADE 3/4 TOCIXITY (Europe)

42

115

14 4

63

23

11

3 3

10

3

51

17

26

00

20

40

60

80

100

% o

f P

atien

ts

CPT-11+5FU/LV 5FU/LV

Neutropenia Neutropenic Fever

Nausea Vomiting Diarrhea Mucositis Asthenia Alopecia Cholinergic Symptoms

GRADES 3/4 TOXICITY(CPT-11+5FU/LV Subgroups, Europe)

29

46

11

4

44

14

0

20

40

60

80

100

Neutropenia Vomiting Diarrhea

CPT-11+weekly (N=54)

CPT-11+biweekly (N=145)

GRADE 3/4 TOXICITY (U.S.)

54

67

31

715

6

158

1610

412

23

13

31

2012 14

43

27

46

2

17

20

20

40

60

80

100

% o

f P

atie

nts

CPT-11+5FU/LV 5FU/LV CPT-11

Neutropenia Neutropenic Fever

Nausea Vomiting Diarrhea MucositisAsthenia Alopecia

DISCONTINUATION2o TO TOXICITY

EUROPECPT-11+5FU/LV 18 (8%)

5FU/LV 5 (3%)

U.S.CPT-11+5FU/LV 17 (7%)

5FU/LV14 (6%)

SUMMARY OF SAFETYCPT-11+5FU/LV REGIMENS

EUROPE U.S.

Neutropenia

Fever withNeutropenia

Nausea =

Vomiting

Diarrhea

Asthenia

Mucositis =

Alopecia

Stop 2o Toxicity =

CONSIDERATIONS FOR APPROVAL

Two large, randomized, well-designed, controlled clinical trials

Significant improvement in survival versus infusional 5FU/LV (AIO and deGramont)

CONSIDERATIONS FOR APPROVAL

Initial trend, then significant improvement in survival versus Mayo Clinic Regimen

CONSIDERATIONS FOR APPROVAL

Acceptable toxicity profile

DOSE/ADMINISTRATION SCHEDULES ?

CPT-11 + 5FU/LV EFFICACY SAFETY

CPT-11 + Weekly bolus + +

CPT-11 + Biweekly CIV +

CPT-11 + Weekly CIV ? ?

REVIEW TEAM

PRIMARYREVIEWER

SECONDARYREVIEWER

MEDICAL Isagani Chico, MD Grant Williams, MD

STATISTICS David Smith, Ph.D. Gang Chen, Ph.D.

PHARMACOLOGY Sandip Roy, Ph.D. Paul Andrews, Ph.D.

BIOPHARM John Duan, Pharm.D. Atiqur Rahman, Ph.D.

CHEMISTRY Sung Kwang Kim, Ph.D. Rebecca Wood, Ph.D.

DSI Gurston Turner, Ph.D.

PROJECT MANAGER Brenda Atkins Dotti Pease