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HC Pitot, KM Rowland, DJ Sargent, PA Philip, EP Mitchell, RM Goldberg, and SR Alberts

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.

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HC Pitot, KM Rowland, DJ Sargent, PA Philip, EP Mitchell, RM Goldberg, and SR Alberts

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  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

  2. N9841: Background • Multicenter phase III trials with every 3 week schedule (CPT-11 2nd line): • CPT-11 vs Supportive care  Median OS 9.2 vs 6.5 mo • 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) • No differences: • Median OS (9.9 mo) • Time to progression • QOL measures • Neutropenia • Toxicity: • 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 • Synergy when combined with 5-FU • Phase II European trials: • Response rate (N=98): 26% • Median OS (N=490): 9.7 mo • 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 2nd line • Secondary: Time to tumor progression (TTP), toxicity, and overall response rate

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

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

  8. N9841: Protocol Therapy • CPT-11 - every 3 wks • 350 mg/m2 d1 (300 mg/m2 if PS=2, >70 yrs, or prior pelvic rad.) • FOLFOX4 - every 2 wks • OXAL 85 mg/m2 over 2 hr d1 • LV 200 mg/m2 over 2 hr d1,2 • 5-FU 400 mg/m2 bolus on d1,2 • 5-FU 600 mg/m2 as 22 hr infusion on d1,2

  9. N9841: Statistical Considerations • 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 • Due to extended accrual, full power achieved after enrollment of 490 pts

  10. N9841: Schema R A N D O M I Z E Progression/ Failure CPT-11 (N=245) FOLFOX4 (N=126) Progression/ Failure FOLFOX4 (N=246) CPT-11 (N=94) Accrual from 10/99 to 12/03

  11. N9841: Patient Characteristics

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

  13. N9841: Overall Survival

  14. N9841: Overall Survival p=0.63

  15. N9841: Time to Tumor Progression

  16. N9841: Time to Tumor Progression p=0.10

  17. N9841: Response Rate

  18. N9841: Toxicity Grade > 3

  19. N9841: Conclusions • For patients with advanced CRC, OS is not significantly different whether 2nd line Rx after failure of 5-FU begins with CPT-11 or FOLFOX4 (HR=1.05, 95% CI 0.9-1.3) • 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 • Notable OS for both arms indicates importance of using all 3 effective agents against CRC

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