2. A POST-MARKETING EVALUATION OF SAFETY CAMPTOSAR + 5-FU/LV FOR FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER A POST-MARKETING EVALUATION OF SAFETY CAMPTOSAR + 5-FU/LV FOR FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER ISAGANI M. CHICO, MD Medical Officer

3. EARLY DEATHS IN IRINOTECAN+5FU/LV EVALUATE DEATHS ONGOING TRIALS REANALYZE LICENSING TRIALS PLAN OF ACTION REGULATORY ACTION

4. DEFINITION OF REGIMENS

5. PLAN OF ACTION EVALUATE DEATHS ONGOING TRIALS REANALYZE LICENSINGTRIALS REGULATORY ACTION “Independent Panel” Pharmacia FDA POST MARKETING EVENTS

6. PLAN OF ACTION EVALUATE DEATHS “Independent Panel” Pharmacia FDA ONGOING TRIALS REANALYZE LICENSING TRIALS REGULATORY ACTION Pharmacia FDA POST MARKETING EVENTS

7. PLAN OF ACTION EVALUATE DEATHS “Independent Panel” Pharmacia FDA ONGOING TRIALS REANALYZE LICENSING TRIALS Pharmacia FDA REGULATORY ACTION Pharmacia POST MARKETING EVENTS

8. FDA REVIEW 1. Early Deaths from NCCTG and CALGB 2. Early Deaths from Licensing Trials 3. Safety in the Licensing Trials

9. EARLY DEATHS NCCTG 9741 AND CALGB 89803

11. DEATH ANALYSIS Methods 30 DAYS FROM LAST TREATMENT (ALL CYCLES)

12. 60 DAYS FROM FIRST TREATMENT (EARLY)  Small time window  Acute toxicity  Interim look at a subset of patients  Subjective determination of causality 30 DAYS FROM LAST TREATMENT (ALL CYCLES)  All cycles considered  Overall toxicity  Complete and mature data  Temporal relationship implies role in death with no judgment of causality DEATH ANALYSIS Definitions DEATH ANALYSIS Definitions

13. EARLY DEATHS Metastatic Disease 6.7% 7.3% 2.0% 2.1% 4.8% 9% 4%

14. EARLY DEATHS Adjuvant Treatment 2.2%

15. LICENSING TRIALS Safety profile of the approved Continuous Infusion IFL could be reassessed Explore signals from early deaths in the cooperative group trials Complete and mature database

16. LICENSING TRIALS: EARLY DEATHS Patient Characteristics

17. LICENSING TRIALS Patient Characteristics

18. LICENSING TRIALS Performance Status

20. SPONSOR’S PROPOSED LABEL CHANGE Populations at Risk Exclude treatment of patients with PS 3 and 4

21. QUESTION QUESTION POPULATIONS AT RISK Should the indication exclude: PS  3 or PS  2? Age  65? Others?

22. LICENSING TRIALS: Safety Profile

23. SPONSOR’S PROPOSED LABEL CHANGE Supportive Care and Monitoring  Fluoroquinolone 7 day course for diarrhea persistent >24 hours, fever accompanying diarrhea, and for ANC <500  Antibiotic support for patients with severe diarrhea if they develop ileus, fever, or severe neutropenia  GCSF for  Grade 2 neutropenia   Weekly assessment during the first cycle of therapy   CBC/Diff within 48 hours prior to treatment

24.  For Grade 2 Diarrhea or Neutropenia = HOLD, No dose reduction  For Grade 3 Diarrhea = Hold until Grade 1, then resume at 1 dose level reduction  Patients must be diarrhea-free for 24 hrs prior to retreatment, SPONSOR’S PROPOSED LABEL CHANGE Dose Modifications

25. MODIFICATIONS ADOPTED BY NCCTG Changes in Dose Modification  For Grade 2 diarrhea or neutropenia = HOLD and reduce one dose level  For Grade 3 diarrhea or neutropenia = HOLD, Reduce two dose levels. Lower Starting Dose of Irinotecan and 5-FU Camptosar 125 mg/m 2 to 100 mg/m 2 5-FU from 500 mg/m 2 to 400 mg/m 2

26. CHOICE OF CONTROL ARM BOLUS IFL vs. CONTINUOUS INFUSION IFL? Continuous Infusion IFL in future studies Continuous Infusion IFL in future studies

27. LICENSING TRIALS: Safety Profile

28. LICENSING TRIALS: Overall Toxicity

29. INFUSION vs. BOLUS 5-FU

31. IRINOTECAN or 5-FU ??

32. POTENTIAL ACTION NO CHANGE

33. POTENTIAL ACTION MINOR CHANGES

34. POTENTIAL ACTION MAJOR CHANGES Requiring randomized controlled trials Requiring randomized controlled trials

35. POTENTIAL ACTION REMOVAL OF BOLUS IFL FROM THE LABEL While studies are ongoing While studies are ongoing Continuous infusion IFL remains in the label Continuous infusion IFL remains in the label