sNDA 20-571

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sNDA 20-571

• Irinotecan as a component of first line
  treatment of patients with metastatic colorectal
  cancer.

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APPROVED SCHEDULES (SINGLE AGENT)

• 125 mg/m2 wkly x 4 Q6 wks
• 350 mg/m2 Q3 wks

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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)

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STUDY DESIGN0038 (U.S.)

• ARM A CPT-11 125 wk x 4 Q 6 wks
  (n226)
• ARM B CPT-11 125 wk x 4 Q 6
  wks(n231) 5FU 500 bolus
  LV 20
• ARM C 5FU 425 daily x 5(n226)
  LV 20

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STUDY DESIGNv303 (EUROPE)
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EFFICACY ENDPOINTS(U.S.)

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

10 TIME TO TUMOR PROGRESSION 2o S URVIVAL
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STUDY DESIGN(Europe)
10 RESPONSE RATE 20 SURVIVAL TTP
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DATA ANALYSIS

• Survival
• Key safety parameters
• Supportiveness of other efficacy endpoints

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INCLUSION CRITERIA
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PATIENT DEMOGRAPHICS(U.S. and Europe)

• Well balanced
• More Rectal Cancer Europe

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DEATHS(Europe)

• Enrollment May 97 to Feb 98
• Cut-off Feb 99 Oct
  99

DEATHS
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SURVIVAL v303 (Europe)
MEDIAN SURVIVAL (Months) February 1999 A
(CPT-115FU/LV 16.8 B (5FU/LV) 14 October
1999 A (CPT-115FU/LV 17.4 B (5FU/LV) 14.1
p 0.028
p 0.032
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DEATHS(U.S.)

• Enrollment May 96 to May 98
• Cut-off Sept 99
  Dec 99

DEATHS
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SURVIVAL 0038 (U.S.)
MEDIAN SURVIVAL (Months) September 1999 B
14.5 C 12.6 A December 1999 B 14.8 C 12.6
A 12.0
p 0.097
p 0.042HR 0.81
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CROSS OVER TO CPT-11

• U.S.
• B CPT-115FU/LV
• C 5FU/LV 40 CPT-11
• A CPT-11
• EUROPE
• A CPT-115FU/LV
• B 5FU/LV 30 CPT-11

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TIME TO TUMOR PROGRESSION(Months)
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TIME TOTREATMENT FAILURE(Months)
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RESPONSE RATE
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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?

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ACCRUAL TREATMENT SUBGROUPS (EUROPE)

• of Patients
• ARM A (CPT-115FU/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

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EFFICACY TREATMENT SUBGROUPS(EUROPE)
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SAFETY REVIEW

• Europe ? CPT-11wkly ? CPT-11 biweekly
• U.S.

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GRADE 3/4 TOCIXITY (Europe)
Neutropenia
Neutropenic Fever
Nausea
Vomiting
Diarrhea
Mucositis
Asthenia
Alopecia
Cholinergic Symptoms
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GRADES 3/4 TOXICITY(CPT-115FU/LV Subgroups,
Europe)
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GRADE 3/4 TOXICITY (U.S.)
Neutropenia
Neutropenic Fever
Nausea
Vomiting
Diarrhea
Mucositis
Asthenia
Alopecia
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DISCONTINUATION2o TO TOXICITY
EUROPE CPT-115FU/LV 18 (8) 5FU/LV 5
(3) U.S. CPT-115FU/LV 17 (7) 5FU/LV 14 (6)
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SUMMARY OF SAFETYCPT-115FU/LV REGIMENS
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CONSIDERATIONS FOR APPROVAL

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

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CONSIDERATIONS FOR APPROVAL

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

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

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CONSIDERATIONS FOR APPROVAL

• Acceptable toxicity profile

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DOSE/ADMINISTRATION SCHEDULES ?
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REVIEW TEAM
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