Download - sNDA 20-571
![Page 1: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/1.jpg)
![Page 2: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/2.jpg)
sNDA 20-571
“Irinotecan as a component of first line treatment of patients with
metastatic colorectal cancer.”
![Page 3: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/3.jpg)
APPROVED SCHEDULES (SINGLE AGENT)
• 125 mg/m2 wkly x 4 Q6 wks
• 350 mg/m2 Q3 wks
![Page 4: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/4.jpg)
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)
![Page 5: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/5.jpg)
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
![Page 6: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/6.jpg)
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
![Page 7: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/7.jpg)
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
![Page 8: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/8.jpg)
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)
![Page 9: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/9.jpg)
DATA ANALYSIS
• Survival
• Key safety parameters
• Supportiveness of other efficacy endpoints
![Page 10: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/10.jpg)
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
![Page 11: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/11.jpg)
PATIENT DEMOGRAPHICS(U.S. and Europe)
• Well balanced
• More Rectal Cancer: Europe
![Page 12: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/12.jpg)
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
![Page 13: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/13.jpg)
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
![Page 14: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/14.jpg)
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
![Page 15: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/15.jpg)
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
![Page 16: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/16.jpg)
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
![Page 17: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/17.jpg)
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
![Page 18: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/18.jpg)
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
![Page 19: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/19.jpg)
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
![Page 20: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/20.jpg)
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?
![Page 21: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/21.jpg)
# 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)
![Page 22: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/22.jpg)
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
![Page 23: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/23.jpg)
SAFETY REVIEW
• Europe CPT-11+wkly CPT-11+ biweekly
• U.S.
![Page 24: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/24.jpg)
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
![Page 25: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/25.jpg)
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)
![Page 26: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/26.jpg)
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
![Page 27: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/27.jpg)
DISCONTINUATION2o TO TOXICITY
EUROPECPT-11+5FU/LV 18 (8%)
5FU/LV 5 (3%)
U.S.CPT-11+5FU/LV 17 (7%)
5FU/LV14 (6%)
![Page 28: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/28.jpg)
SUMMARY OF SAFETYCPT-11+5FU/LV REGIMENS
EUROPE U.S.
Neutropenia
Fever withNeutropenia
Nausea =
Vomiting
Diarrhea
Asthenia
Mucositis =
Alopecia
Stop 2o Toxicity =
![Page 29: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/29.jpg)
CONSIDERATIONS FOR APPROVAL
Two large, randomized, well-designed, controlled clinical trials
![Page 30: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/30.jpg)
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
![Page 31: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/31.jpg)
CONSIDERATIONS FOR APPROVAL
Acceptable toxicity profile
![Page 32: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/32.jpg)
DOSE/ADMINISTRATION SCHEDULES ?
CPT-11 + 5FU/LV EFFICACY SAFETY
CPT-11 + Weekly bolus + +
CPT-11 + Biweekly CIV +
CPT-11 + Weekly CIV ? ?
![Page 33: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/33.jpg)
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
![Page 34: sNDA 20-571](https://reader035.vdocuments.net/reader035/viewer/2022081419/56815b17550346895dc8c866/html5/thumbnails/34.jpg)