1 N9841: A Randomized Phase III Equivalence Trial of Irinotecan (CPT-11) versus FOLFOX4 in Patients with Advanced Colorectal Carcinoma Previously Treated with 5-Fluorouracil HC Pitot, KM Rowland, DJ Sargent, PA Philip, EP Mitchell, RM Goldberg, and SR Alberts NCCTG, SWOG and ECOG HC Pitot, KM Rowland, DJ Sargent, PA Philip, EP Mitchell, RM Goldberg, and SR Alberts NCCTG, SWOG and ECOG

2 N9841: Background Multicenter phase III trials with every 3 week schedule (CPT-11 2 nd line): Multicenter phase III trials with every 3 week schedule (CPT-11 2 nd line): CPT-11 vs Supportive care CPT-11 vs Supportive care  Median OS 9.2 vs 6.5 mo CPT-11 vs Infusional 5-FU CPT-11 vs Infusional 5-FU  Median OS 10.8 vs 8.5 mo Multicenter phase III trials with every 3 week schedule (CPT-11 2 nd line): Multicenter phase III trials with every 3 week schedule (CPT-11 2 nd line): CPT-11 vs Supportive care CPT-11 vs Supportive care  Median OS 9.2 vs 6.5 mo CPT-11 vs Infusional 5-FU CPT-11 vs Infusional 5-FU  Median OS 10.8 vs 8.5 mo Cunningham et al Lancet 1998 Rougier et al Lancet 1998

3 N9841: Background CPT-11: Weekly schedule compared to every 3 week (N=291) CPT-11: Weekly schedule compared to every 3 week (N=291) No differences: No differences: Median OS (9.9 mo) Median OS (9.9 mo) Time to progression Time to progression QOL measures QOL measures Neutropenia Neutropenia Toxicity: Toxicity: Gr 3/4 diarrhea less common with every 3 week Rx Gr 3/4 diarrhea less common with every 3 week Rx CPT-11: Weekly schedule compared to every 3 week (N=291) CPT-11: Weekly schedule compared to every 3 week (N=291) No differences: No differences: Median OS (9.9 mo) Median OS (9.9 mo) Time to progression Time to progression QOL measures QOL measures Neutropenia Neutropenia Toxicity: Toxicity: Gr 3/4 diarrhea less common with every 3 week Rx Gr 3/4 diarrhea less common with every 3 week Rx Fuchs et al, J Clin Oncol 2003

4 N9841: Background Oxaliplatin active as single agent or combined with 5-FU/LV in pts with progressing CRC Oxaliplatin active as single agent or combined with 5-FU/LV in pts with progressing CRC Synergy when combined with 5-FU Synergy when combined with 5-FU Phase II European trials: Phase II European trials: Response rate (N=98): 26% Response rate (N=98): 26% Median OS (N=490): 9.7 mo Median OS (N=490): 9.7 mo Toxicity: sensory neuropathy Toxicity: sensory neuropathy Oxaliplatin active as single agent or combined with 5-FU/LV in pts with progressing CRC Oxaliplatin active as single agent or combined with 5-FU/LV in pts with progressing CRC Synergy when combined with 5-FU Synergy when combined with 5-FU Phase II European trials: Phase II European trials: Response rate (N=98): 26% Response rate (N=98): 26% Median OS (N=490): 9.7 mo Median OS (N=490): 9.7 mo Toxicity: sensory neuropathy Toxicity: sensory neuropathy Bleiberg et al Sem Oncol 1998

5 N9841: Objectives Primary: Equivalence of overall survival (OS) of patients treated with FOLFOX4 or CPT-11 in 2 nd line Primary: Equivalence of overall survival (OS) of patients treated with FOLFOX4 or CPT-11 in 2 nd line Secondary: Time to tumor progression (TTP), toxicity, and overall response rate Secondary: Time to tumor progression (TTP), toxicity, and overall response rate Primary: Equivalence of overall survival (OS) of patients treated with FOLFOX4 or CPT-11 in 2 nd line Primary: Equivalence of overall survival (OS) of patients treated with FOLFOX4 or CPT-11 in 2 nd line Secondary: Time to tumor progression (TTP), toxicity, and overall response rate Secondary: Time to tumor progression (TTP), toxicity, and overall response rate

6 N9841: Main Inclusion Criteria Progressive metastatic CRC: Progressive metastatic CRC: Prior 5-FU based chemo Prior 5-FU based chemo < 6 mo from adjuvant 5-FU Rx < 6 mo from adjuvant 5-FU Rx Histologically confirmed CRC Histologically confirmed CRC ECOG PS of 0,1 or 2 ECOG PS of 0,1 or 2 Adequate organ function Adequate organ function Signed informed consent Signed informed consent Progressive metastatic CRC: Progressive metastatic CRC: Prior 5-FU based chemo Prior 5-FU based chemo < 6 mo from adjuvant 5-FU Rx < 6 mo from adjuvant 5-FU Rx Histologically confirmed CRC Histologically confirmed CRC ECOG PS of 0,1 or 2 ECOG PS of 0,1 or 2 Adequate organ function Adequate organ function Signed informed consent Signed informed consent

7 N9841: Main Exclusion Criteria > 1 prior chemo for advanced CRC > 1 prior chemo for advanced CRC Prior CPT-11 or oxaliplatin Prior CPT-11 or oxaliplatin CNS metastases CNS metastases Prior RT to >25% of bone marrow Prior RT to >25% of bone marrow Pre-existing neuropathy (>Gr 2) Pre-existing neuropathy (>Gr 2) > 3 loose stools daily > 3 loose stools daily > 1 prior chemo for advanced CRC > 1 prior chemo for advanced CRC Prior CPT-11 or oxaliplatin Prior CPT-11 or oxaliplatin CNS metastases CNS metastases Prior RT to >25% of bone marrow Prior RT to >25% of bone marrow Pre-existing neuropathy (>Gr 2) Pre-existing neuropathy (>Gr 2) > 3 loose stools daily > 3 loose stools daily

8 N9841: Protocol Therapy CPT-11 - every 3 wks CPT-11 - every 3 wks 350 mg/m 2 d1 (300 mg/m 2 if PS=2, >70 yrs, or prior pelvic rad.) 350 mg/m 2 d1 (300 mg/m 2 if PS=2, >70 yrs, or prior pelvic rad.) FOLFOX4 - every 2 wks FOLFOX4 - every 2 wks OXAL 85 mg/m 2 over 2 hr d1 OXAL 85 mg/m 2 over 2 hr d1 LV 200 mg/m 2 over 2 hr d1,2 LV 200 mg/m 2 over 2 hr d1,2 5-FU 400 mg/m 2 bolus on d1,2 5-FU 400 mg/m 2 bolus on d1,2 5-FU 600 mg/m 2 as 22 hr infusion on d1,2 5-FU 600 mg/m 2 as 22 hr infusion on d1,2 CPT-11 - every 3 wks CPT-11 - every 3 wks 350 mg/m 2 d1 (300 mg/m 2 if PS=2, >70 yrs, or prior pelvic rad.) 350 mg/m 2 d1 (300 mg/m 2 if PS=2, >70 yrs, or prior pelvic rad.) FOLFOX4 - every 2 wks FOLFOX4 - every 2 wks OXAL 85 mg/m 2 over 2 hr d1 OXAL 85 mg/m 2 over 2 hr d1 LV 200 mg/m 2 over 2 hr d1,2 LV 200 mg/m 2 over 2 hr d1,2 5-FU 400 mg/m 2 bolus on d1,2 5-FU 400 mg/m 2 bolus on d1,2 5-FU 600 mg/m 2 as 22 hr infusion on d1,2 5-FU 600 mg/m 2 as 22 hr infusion on d1,2

9 N9841: Statistical Considerations Compare OS of 2 arms for non-inferiority of FOLFOX4 Compare OS of 2 arms for non-inferiority of FOLFOX4 Planned sample size of 560 provide 95% power to detect inferiority if HR = 1.33 Planned sample size of 560 provide 95% power to detect inferiority if HR = 1.33 Due to extended accrual, full power achieved after enrollment of 490 pts Due to extended accrual, full power achieved after enrollment of 490 pts Compare OS of 2 arms for non-inferiority of FOLFOX4 Compare OS of 2 arms for non-inferiority of FOLFOX4 Planned sample size of 560 provide 95% power to detect inferiority if HR = 1.33 Planned sample size of 560 provide 95% power to detect inferiority if HR = 1.33 Due to extended accrual, full power achieved after enrollment of 490 pts Due to extended accrual, full power achieved after enrollment of 490 pts

10 N9841: Schema RANDOMIZERANDOMIZE Accrual from 10/99 to 12/03 CPT-11 (N=245) FOLFOX4 (N=246) CPT-11 (N=94) FOLFOX4 (N=126) Progression/ Failure Progression/ Failure

11 N9841: Patient Characteristics CPT-11(N=245)FOLFOX4(N=246) ECOG PS %95% Median Age 63 yrs Male Gender 62%55% Failed Adj. 5-FU 42%40% 1 o Indicator Hepatic Hepatic53%55% Pulmonary Pulmonary17%20%

12 N9841: 3rd Line Therapy 3rd Line Therapy: 220 pts (45%) CPT-11 (N=94, 38%) FOLFOX4 (N=126, 51%) Crossover at Progression/ Failure Results to be presented by Rowland et al, Abstract #3519

13 N9841: Overall Survival CPT-11 (N=245) FOLFOX4 (N=246) Median Overall Survival (mo) Hazard Ratio p value

14 N9841: Overall Survival p=0.63

15 N9841: Time to Tumor Progression CPT-11 (N=245) FOLFOX4 (N=246) Median TTP (mo) Hazard Ratio p value

16 N9841: Time to Tumor Progression p=0.10

17 N9841: Response Rate CPT-11 (N=245) FOLFOX4 (N=246) Response Rate 15%27% 95% CI % % p value --<0.01

18 N9841: Toxicity Grade > 3

19 N9841: Conclusions For patients with advanced CRC, OS is not significantly different whether 2 nd line Rx after failure of 5-FU begins with CPT-11 or FOLFOX4 (HR=1.05, 95% CI ) For patients with advanced CRC, OS is not significantly different whether 2 nd line Rx after failure of 5-FU begins with CPT-11 or FOLFOX4 (HR=1.05, 95% CI ) Toxicity profile favors FOLFOX4 Toxicity profile favors FOLFOX4 For patients with advanced CRC, OS is not significantly different whether 2 nd line Rx after failure of 5-FU begins with CPT-11 or FOLFOX4 (HR=1.05, 95% CI ) For patients with advanced CRC, OS is not significantly different whether 2 nd line Rx after failure of 5-FU begins with CPT-11 or FOLFOX4 (HR=1.05, 95% CI ) Toxicity profile favors FOLFOX4 Toxicity profile favors FOLFOX4

20 N9841: Conclusions (cont.) 2nd line FOLFOX4 produces higher RR (27% vs 15%) and trend toward longer TTP compared with CPT-11 2nd line FOLFOX4 produces higher RR (27% vs 15%) and trend toward longer TTP compared with CPT-11 Notable OS for both arms indicates importance of using all 3 effective agents against CRC Notable OS for both arms indicates importance of using all 3 effective agents against CRC 2nd line FOLFOX4 produces higher RR (27% vs 15%) and trend toward longer TTP compared with CPT-11 2nd line FOLFOX4 produces higher RR (27% vs 15%) and trend toward longer TTP compared with CPT-11 Notable OS for both arms indicates importance of using all 3 effective agents against CRC Notable OS for both arms indicates importance of using all 3 effective agents against CRC

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