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N9841: A Randomized Phase III N9841: A Randomized Phase III Equivalence Trial of Irinotecan Equivalence Trial of Irinotecan

(CPT-11) versus FOLFOX4 in Patients (CPT-11) versus FOLFOX4 in Patients with Advanced Colorectal Carcinoma with Advanced Colorectal Carcinoma

Previously Treated with Previously Treated with

5-Fluorouracil5-Fluorouracil

N9841: A Randomized Phase III N9841: A Randomized Phase III Equivalence Trial of Irinotecan Equivalence Trial of Irinotecan

(CPT-11) versus FOLFOX4 in Patients (CPT-11) versus FOLFOX4 in Patients with Advanced Colorectal Carcinoma with Advanced Colorectal Carcinoma

Previously Treated with Previously Treated with

5-Fluorouracil5-Fluorouracil

HC Pitot, KM Rowland, HC Pitot, KM Rowland, DJ Sargent, PA Philip, EP Mitchell, RM DJ Sargent, PA Philip, EP Mitchell, RM

Goldberg, and SR AlbertsGoldberg, and SR Alberts

NCCTG, SWOG and ECOGNCCTG, SWOG and ECOG

HC Pitot, KM Rowland, HC Pitot, KM Rowland, DJ Sargent, PA Philip, EP Mitchell, RM DJ Sargent, PA Philip, EP Mitchell, RM

Goldberg, and SR AlbertsGoldberg, and SR Alberts

NCCTG, SWOG and ECOGNCCTG, SWOG and ECOG

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N9841: BackgroundN9841: BackgroundN9841: BackgroundN9841: Background

• Multicenter phase III trials withMulticenter phase III trials with every 3 week schedule (CPT-11 2every 3 week schedule (CPT-11 2ndnd line): line):• CPT-11 vs Supportive careCPT-11 vs Supportive care

Median OS 9.2 vs 6.5 moMedian OS 9.2 vs 6.5 mo

• CPT-11 vs Infusional 5-FUCPT-11 vs Infusional 5-FU Median OS 10.8 vs 8.5 moMedian OS 10.8 vs 8.5 mo

• Multicenter phase III trials withMulticenter phase III trials with every 3 week schedule (CPT-11 2every 3 week schedule (CPT-11 2ndnd line): line):• CPT-11 vs Supportive careCPT-11 vs Supportive care

Median OS 9.2 vs 6.5 moMedian OS 9.2 vs 6.5 mo

• CPT-11 vs Infusional 5-FUCPT-11 vs Infusional 5-FU Median OS 10.8 vs 8.5 moMedian OS 10.8 vs 8.5 mo

Cunningham et al Lancet 1998

Rougier et al Lancet 1998

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N9841: BackgroundN9841: BackgroundN9841: BackgroundN9841: Background• CPT-11: Weekly schedule compared to CPT-11: Weekly schedule compared to

every 3 week (N=291)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 • NeutropeniaNeutropenia

• Toxicity: Toxicity: • Gr 3/4 diarrhea less common with every Gr 3/4 diarrhea less common with every

3 week Rx 3 week Rx

• CPT-11: Weekly schedule compared to CPT-11: Weekly schedule compared to every 3 week (N=291)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 • NeutropeniaNeutropenia

• Toxicity: Toxicity: • Gr 3/4 diarrhea less common with every Gr 3/4 diarrhea less common with every

3 week Rx 3 week Rx

Fuchs et al, J Clin Oncol 2003

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N9841: BackgroundN9841: BackgroundN9841: BackgroundN9841: Background• Oxaliplatin active as single agent or Oxaliplatin active as single agent or

combined with 5-FU/LV in pts with combined with 5-FU/LV in pts with progressing CRCprogressing CRC

• Synergy when combined with 5-FUSynergy 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 moMedian OS (N=490): 9.7 mo• Toxicity: sensory neuropathy Toxicity: sensory neuropathy

• Oxaliplatin active as single agent or Oxaliplatin active as single agent or combined with 5-FU/LV in pts with combined with 5-FU/LV in pts with progressing CRCprogressing CRC

• Synergy when combined with 5-FUSynergy 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 moMedian OS (N=490): 9.7 mo• Toxicity: sensory neuropathy Toxicity: sensory neuropathy

Bleiberg et al Sem Oncol 1998

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N9841: ObjectivesN9841: Objectives N9841: ObjectivesN9841: Objectives

• Primary: Primary: EquivalenceEquivalence of overall of overall survival (OS) of patients treated with survival (OS) of patients treated with FOLFOX4 or CPT-11 in 2FOLFOX4 or CPT-11 in 2ndnd line line

• Secondary: Time to tumor progression Secondary: Time to tumor progression (TTP), toxicity, and overall response (TTP), toxicity, and overall response raterate

• Primary: Primary: EquivalenceEquivalence of overall of overall survival (OS) of patients treated with survival (OS) of patients treated with FOLFOX4 or CPT-11 in 2FOLFOX4 or CPT-11 in 2ndnd line line

• Secondary: Time to tumor progression Secondary: Time to tumor progression (TTP), toxicity, and overall response (TTP), toxicity, and overall response raterate

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N9841: Main Inclusion CriteriaN9841: Main Inclusion CriteriaN9841: Main Inclusion CriteriaN9841: Main Inclusion Criteria

• Progressive metastatic CRC:Progressive metastatic CRC:• Prior 5-FU based chemoPrior 5-FU based chemo• << 6 mo from adjuvant 5-FU Rx 6 mo from adjuvant 5-FU Rx

• Histologically confirmed CRCHistologically confirmed CRC

• ECOG PS of 0,1 or 2ECOG PS of 0,1 or 2

• Adequate organ functionAdequate organ function

• Signed informed consentSigned informed consent

• Progressive metastatic CRC:Progressive metastatic CRC:• Prior 5-FU based chemoPrior 5-FU based chemo• << 6 mo from adjuvant 5-FU Rx 6 mo from adjuvant 5-FU Rx

• Histologically confirmed CRCHistologically confirmed CRC

• ECOG PS of 0,1 or 2ECOG PS of 0,1 or 2

• Adequate organ functionAdequate organ function

• Signed informed consentSigned informed consent

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N9841: Main Exclusion CriteriaN9841: Main Exclusion CriteriaN9841: Main Exclusion CriteriaN9841: Main Exclusion Criteria

• > 1 prior chemo for advanced CRC> 1 prior chemo for advanced CRC

• Prior CPT-11 or oxaliplatinPrior CPT-11 or oxaliplatin

• CNS metastasesCNS metastases

• Prior RT to >25% of bone marrowPrior RT to >25% of bone marrow

• Pre-existing neuropathy (Pre-existing neuropathy (>>Gr 2)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 oxaliplatinPrior CPT-11 or oxaliplatin

• CNS metastasesCNS metastases

• Prior RT to >25% of bone marrowPrior RT to >25% of bone marrow

• Pre-existing neuropathy (Pre-existing neuropathy (>>Gr 2)Gr 2)

• > 3 loose stools daily> 3 loose stools daily

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N9841: Protocol TherapyN9841: Protocol TherapyN9841: Protocol TherapyN9841: Protocol Therapy

• CPT-11 - every 3 wks CPT-11 - every 3 wks • 350 mg/m350 mg/m22 d1 d1

(300 mg/m(300 mg/m22 if PS=2, if PS=2, >>70 yrs, or prior pelvic rad.)70 yrs, or prior pelvic rad.)

• FOLFOX4 - every 2 wksFOLFOX4 - every 2 wks• OXAL 85 mg/mOXAL 85 mg/m22 over 2 hr d1 over 2 hr d1• LV 200 mg/mLV 200 mg/m22 over 2 hr d1,2 over 2 hr d1,2• 5-FU 400 mg/m5-FU 400 mg/m22 bolus on d1,2 bolus on d1,2• 5-FU 600 mg/m5-FU 600 mg/m22 as 22 hr infusion on d1,2 as 22 hr infusion on d1,2

• CPT-11 - every 3 wks CPT-11 - every 3 wks • 350 mg/m350 mg/m22 d1 d1

(300 mg/m(300 mg/m22 if PS=2, if PS=2, >>70 yrs, or prior pelvic rad.)70 yrs, or prior pelvic rad.)

• FOLFOX4 - every 2 wksFOLFOX4 - every 2 wks• OXAL 85 mg/mOXAL 85 mg/m22 over 2 hr d1 over 2 hr d1• LV 200 mg/mLV 200 mg/m22 over 2 hr d1,2 over 2 hr d1,2• 5-FU 400 mg/m5-FU 400 mg/m22 bolus on d1,2 bolus on d1,2• 5-FU 600 mg/m5-FU 600 mg/m22 as 22 hr infusion on d1,2 as 22 hr infusion on d1,2

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N9841: Statistical N9841: Statistical ConsiderationsConsiderations

N9841: Statistical N9841: Statistical ConsiderationsConsiderations

• Compare OS of 2 arms for non-inferiority Compare OS of 2 arms for non-inferiority of FOLFOX4of FOLFOX4

• Planned sample size of 560 provide 95% Planned sample size of 560 provide 95% power to detect inferiority if HR = 1.33power to detect inferiority if HR = 1.33

• Due to extended accrual, full power Due to extended accrual, full power achieved after enrollment of 490 ptsachieved after enrollment of 490 pts

• Compare OS of 2 arms for non-inferiority Compare OS of 2 arms for non-inferiority of FOLFOX4of FOLFOX4

• Planned sample size of 560 provide 95% Planned sample size of 560 provide 95% power to detect inferiority if HR = 1.33power to detect inferiority if HR = 1.33

• Due to extended accrual, full power Due to extended accrual, full power achieved after enrollment of 490 ptsachieved after enrollment of 490 pts

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N9841: SchemaN9841: SchemaN9841: SchemaN9841: Schema

RANDOMIZE

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

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N9841: Patient CharacteristicsN9841: Patient CharacteristicsN9841: Patient CharacteristicsN9841: Patient Characteristics

CPT-11CPT-11(N=245)(N=245)

FOLFOX4FOLFOX4(N=246)(N=246)

ECOG PS 0-1ECOG PS 0-1 96%96% 95%95%

Median AgeMedian Age 63 yrs63 yrs 63 yrs63 yrs

Male GenderMale Gender 62%62% 55%55%

Failed Adj. 5-FUFailed Adj. 5-FU 42%42% 40%40%

11oo Indicator Indicator

HepaticHepatic 53%53% 55%55%

PulmonaryPulmonary 17%17% 20%20%

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N9841: 3rd Line TherapyN9841: 3rd Line TherapyN9841: 3rd Line TherapyN9841: 3rd Line Therapy3rd Line Therapy: 220 pts (45%)

CPT-11 (N=94, 38%)

FOLFOX4(N=126, 51%)

Crossover atProgression/

Failure

Results to be presented by Rowland et al, Abstract #3519

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N9841: Overall SurvivalN9841: Overall SurvivalN9841: Overall SurvivalN9841: Overall Survival

CPT-11 CPT-11 (N=245)(N=245)

FOLFOX4 FOLFOX4 (N=246)(N=246)

Median Overall Median Overall Survival (mo)Survival (mo) 14.714.7 13.513.5

Hazard RatioHazard Ratio ---- 1.051.05

p valuep value ---- 0.630.63

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N9841: Overall SurvivalN9841: Overall SurvivalN9841: Overall SurvivalN9841: Overall Survival

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24Months from Registration

% Alive

CPT-11 N = 245

FOLFOX N = 246

p=0.63

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N9841: Time to Tumor N9841: Time to Tumor ProgressionProgression

N9841: Time to Tumor N9841: Time to Tumor ProgressionProgression

CPT-11 CPT-11 (N=245)(N=245)

FOLFOX4 FOLFOX4 (N=246)(N=246)

Median TTP (mo)Median TTP (mo) 4.04.0 5.25.2

Hazard RatioHazard Ratio ---- 1.171.17

p valuep value ---- 0.100.10

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N9841: Time to Tumor ProgressionN9841: Time to Tumor ProgressionN9841: Time to Tumor ProgressionN9841: Time to Tumor Progression

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18

Months from Registration

% Progression Free

CPT-11 N = 245

FOLFOX N = 246

p=0.10

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N9841: Response RateN9841: Response RateN9841: Response RateN9841: Response Rate

CPT-11 CPT-11 (N=245)(N=245)

FOLFOX4 FOLFOX4 (N=246)(N=246)

Response RateResponse Rate 15%15% 27%27%

95% CI95% CI 10 - 20%10 - 20% 22 - 34%22 - 34%

p valuep value ---- <0.01<0.01

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N9841: Toxicity Grade N9841: Toxicity Grade >> 3 3N9841: Toxicity Grade N9841: Toxicity Grade >> 3 3

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N9841: ConclusionsN9841: ConclusionsN9841: ConclusionsN9841: Conclusions

• For patients with advanced CRC, OS is not For patients with advanced CRC, OS is not significantly different whether 2significantly different whether 2ndnd line Rx line Rx after failure of 5-FU begins with after failure of 5-FU begins with CPT-11 or FOLFOX4 CPT-11 or FOLFOX4 (HR=1.05, 95% CI 0.9-1.3)(HR=1.05, 95% CI 0.9-1.3)

• Toxicity profile favors FOLFOX4Toxicity profile favors FOLFOX4

• For patients with advanced CRC, OS is not For patients with advanced CRC, OS is not significantly different whether 2significantly different whether 2ndnd line Rx line Rx after failure of 5-FU begins with after failure of 5-FU begins with CPT-11 or FOLFOX4 CPT-11 or FOLFOX4 (HR=1.05, 95% CI 0.9-1.3)(HR=1.05, 95% CI 0.9-1.3)

• Toxicity profile favors FOLFOX4Toxicity profile favors FOLFOX4

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N9841: Conclusions (cont.)N9841: Conclusions (cont.)N9841: Conclusions (cont.)N9841: Conclusions (cont.)

• 2nd line FOLFOX4 produces higher RR (27% 2nd line FOLFOX4 produces higher RR (27% vs 15%) and trend toward longer TTP vs 15%) and trend toward longer TTP compared with CPT-11compared with CPT-11

• Notable OS for both arms indicates Notable OS for both arms indicates importance of using all 3 effective agents importance of using all 3 effective agents against CRCagainst CRC

• 2nd line FOLFOX4 produces higher RR (27% 2nd line FOLFOX4 produces higher RR (27% vs 15%) and trend toward longer TTP vs 15%) and trend toward longer TTP compared with CPT-11compared with CPT-11

• Notable OS for both arms indicates Notable OS for both arms indicates importance of using all 3 effective agents importance of using all 3 effective agents against CRCagainst CRC

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