ISAGANI M. CHICO, MD Medical Officer

1. A POST-MARKETING EVALUATION OF SAFETYCAMPTOSAR + 5-FU/LV FORFIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER ISAGANI M. CHICO, MD Medical Officer

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

3. DEFINITION OF REGIMENS

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

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

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

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

8. EARLY DEATHS NCCTG 9741 AND CALGB 89803

9. EARLY DEATHS NCCTG 9741 AND CALGB 89803

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

11. 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

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

13. EARLY DEATHS Adjuvant Treatment 2.2%

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

15. LICENSING TRIALS: EARLY DEATHS Patient Characteristics

16. LICENSING TRIALS Patient Characteristics

17. LICENSING TRIALSPerformance Status

18. LICENSING TRIALSPerformance Status

19. SPONSOR’S PROPOSED LABEL CHANGEPopulations at Risk Exclude treatment of patients with PS 3 and 4

20. QUESTIONPOPULATIONS AT RISK Should the indication exclude: PS  3 or PS 2? Age  65? Others?

21. LICENSING TRIALS: Safety Profile

22. SPONSOR’S PROPOSED LABEL CHANGESupportive 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

23. SPONSOR’S PROPOSED LABEL CHANGE Dose Modifications • 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,

24. MODIFICATIONS ADOPTED BY NCCTG Lower Starting Dose of Irinotecan and 5-FU • Camptosar 125 mg/m2 to 100 mg/m2 • 5-FU from 500 mg/m2 to 400 mg/m2 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.

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

26. LICENSING TRIALS: Safety Profile

27. LICENSING TRIALS:Overall Toxicity

28. INFUSION vs. BOLUS 5-FU

29. INFUSION vs. BOLUS 5-FU

30. IRINOTECAN or 5-FU ??

31. POTENTIAL ACTION NO CHANGE

32. POTENTIAL ACTION MINOR CHANGES

33. POTENTIAL ACTION MAJOR CHANGES • Requiring randomized controlled trials

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