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sNDA 20-571

sNDA 20-571. “Irinotecan as a component of first line treatment of patients with metastatic colorectal cancer.”. APPROVED SCHEDULES (SINGLE AGENT). 125 mg/m 2 wkly x 4 Q6 wks 350 mg/m 2 Q3 wks. PROPOSED SCHEDULES (CPT-11 + 5FU/LV). CPT-11+ BOLUS CPT-11 + 5FU/LV weekly x 4 ( Saltz )

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sNDA 20-571

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  1. sNDA 20-571 “Irinotecan as a component of first line treatment of patients with metastatic colorectal cancer.”

  2. APPROVED SCHEDULES(SINGLE AGENT) • 125 mg/m2 wkly x 4 Q6 wks • 350 mg/m2 Q3 wks

  3. 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)

  4. 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

  5. STUDY DESIGNv303 (EUROPE)

  6. 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

  7. STUDY DESIGN(Europe) 10: RESPONSE RATE 20: SURVIVAL TTP

  8. DATA ANALYSIS • Survival • Key safety parameters • Supportiveness of other efficacy endpoints

  9. INCLUSION CRITERIA

  10. PATIENT DEMOGRAPHICS(U.S. and Europe) • Well balanced • More Rectal Cancer: Europe

  11. DEATHS(Europe) • Enrollment: May 97 to Feb 98 • Cut-off: Feb 99 Oct 99 % DEATHS

  12. SURVIVAL v303 (Europe) MEDIAN SURVIVAL (Months) February 1999 A (CPT-11+5FU/LV = 16.8 B (5FU/LV) = 14 October 1999 A (CPT-11+5FU/LV = 17.4 B (5FU/LV) =14.1 p = 0.028 p = 0.032

  13. DEATHS(U.S.) • Enrollment: May 96 to May 98 • Cut-off: Sept 99 Dec 99 % DEATHS

  14. 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

  15. 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

  16. TIME TO TUMOR PROGRESSION(Months)

  17. TIME TOTREATMENT FAILURE(Months)

  18. RESPONSE RATE

  19. 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? SUMMARY OF EFFICACY

  20. ACCRUAL: TREATMENT SUBGROUPS(EUROPE) # 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

  21. EFFICACY: TREATMENT SUBGROUPS(EUROPE)

  22. SAFETY REVIEW • Europe CPT-11+wkly  CPT-11+ biweekly • U.S.

  23. GRADE 3/4 TOCIXITY (Europe) Neutropenia Neutropenic Fever Nausea Vomiting Diarrhea Mucositis Asthenia Alopecia Cholinergic Symptoms

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

  25. GRADE 3/4 TOXICITY(U.S.) Neutropenia Neutropenic Fever Nausea Vomiting Diarrhea Asthenia Alopecia Mucositis

  26. DISCONTINUATION2o TO TOXICITY EUROPE CPT-11+5FU/LV 18 (8%) 5FU/LV 5 (3%) U.S. CPT-11+5FU/LV 17 (7%) 5FU/LV 14 (6%)

  27. SUMMARY OF SAFETYCPT-11+5FU/LV REGIMENS

  28. Two large, randomized, well-designed, controlled clinical trials CONSIDERATIONS FOR APPROVAL

  29. Significant improvement in survival versus infusional 5FU/LV (AIO and deGramont) Initial trend, then significant improvement in survival versus Mayo Clinic Regimen CONSIDERATIONS FOR APPROVAL

  30. CONSIDERATIONS FOR APPROVAL • Acceptable toxicity profile

  31. DOSE/ADMINISTRATION SCHEDULES ?

  32. REVIEW TEAM

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