1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar Pharmacia...
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Transcript of 1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar Pharmacia...
![Page 1: 1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar Pharmacia & Upjohn First-Line Therapy of Metastatic Colorectal.](https://reader036.fdocuments.us/reader036/viewer/2022070308/551c2950550346a34f8b5f86/html5/thumbnails/1.jpg)
11
(Irinotecan, CPT-11)(Irinotecan, CPT-11)
Oncologic Drugs Advisory Committee ReviewOncologic Drugs Advisory Committee ReviewMarch 16, 2000March 16, 2000
CamptosarCamptosar
Pharmacia & UpjohnPharmacia & Upjohn
First-Line Therapy of Metastatic Colorectal CancerFirst-Line Therapy of Metastatic Colorectal Cancer
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Presentation AgendaPresentation Agenda
BackgroundBackground
2 Pivotal Phase III Controlled Clinical Trials2 Pivotal Phase III Controlled Clinical Trials– Improved Tumor ControlImproved Tumor Control
– Improved SurvivalImproved Survival
Summary and ConclusionsSummary and Conclusions
Q&AQ&A
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CPT-11 Presentation TeamCPT-11 Presentation Team
FunctionFunction NameName AffiliationAffiliation
MedicalMedical Langdon Miller, MDLangdon Miller, MD P&UP&UPaula Locker, MSPaula Locker, MS P&UP&UGabriela Gruia, MDGabriela Gruia, MD AventisAventis
BiostatisticalBiostatistical Nicoletta Pirotta, MSNicoletta Pirotta, MS P&UP&UGary Elfring, MSGary Elfring, MS P&UP&ULucile Awad, MSLucile Awad, MS AventisAventis
PharmacologyPharmacology Larry Schaaf, PhDLarry Schaaf, PhD P&UP&U
InvestigatorsInvestigators Leonard Saltz, MDLeonard Saltz, MD MSKCCMSKCCJean-YvesJean-Yves Douillard, MD Douillard, MD C GauducheauC GauducheauHanjochenHanjochen Wilke, MDWilke, MD K Essen-MitteK Essen-Mitte
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Background
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Development of metastases:Development of metastases:– 20% of patients have metastatic disease at presentation20% of patients have metastatic disease at presentation
– 40% of all patients will ultimately develop metastases40% of all patients will ultimately develop metastases
Deaths due to metastatic disease: 57,000 patientsDeaths due to metastatic disease: 57,000 patients
Standard first-line treatment: 5-fluorouracil (5-FU)Standard first-line treatment: 5-fluorouracil (5-FU)
Colorectal Cancer in 2000Colorectal Cancer in 2000
US Incidence: 130,000 patientsUS Incidence: 130,000 patients– 95,000 with colon cancer95,000 with colon cancer
– 35,000 with rectal cancer35,000 with rectal cancer
American Cancer Society. American Cancer Society. Cancer Facts & Figures 2000. Cancer Facts & Figures 2000.
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66
11 mo 11.5 mo
0
6
12
18
5-FUAlone
(N=578)
5-FULV
(N=803)
Survival (median)Survival (median)
5-FU Therapy: With and Without LV5-FU Therapy: With and Without LV
Adding LV to 5-FU significantly Adding LV to 5-FU significantly improves response rate but not survivalimproves response rate but not survival
Adding LV to 5-FU significantly Adding LV to 5-FU significantly improves response rate but not survivalimproves response rate but not survival
Meta-analysis Group in Cancer.Meta-analysis Group in Cancer. J Clin Oncol J Clin Oncol. 1992;10:896-903. 1992;10:896-903
Meta-analysis of 9 randomized trials (N=1,381)Meta-analysis of 9 randomized trials (N=1,381)
11%
23%
0%
10%
20%
30%
40%
5-FUAlone
(N=578)
5-FULV
(N=803)
Response RateResponse Rate
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5-FU Therapy: Infusional vs Bolus5-FU Therapy: Infusional vs Bolus
Infusional 5-FU significantly increases response Infusional 5-FU significantly increases response rate but median survival remains 12 monthsrate but median survival remains 12 months
Infusional 5-FU significantly increases response Infusional 5-FU significantly increases response rate but median survival remains 12 monthsrate but median survival remains 12 months
Meta-analysis Group in Cancer. Meta-analysis Group in Cancer. J Clin OncolJ Clin Oncol. 1998;16:301-308.. 1998;16:301-308.
Meta-analysis of 6 randomized trials (N=1,219)Meta-analysis of 6 randomized trials (N=1,219)
14%
22%
0%
10%
20%
30%
40%
5-FUBolus
(N=612)
5-FUInfusion(N=607)
Response RateResponse Rate
11.3 mo 12.1 mo
0
6
12
18
5-FUBolus
(N=612)
5-FUInfusion(N=607)
Survival (median)Survival (median)
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Novel agent with a new mechanism of action neededNovel agent with a new mechanism of action needed
CPT-11 Therapy of Colorectal CancerCPT-11 Therapy of Colorectal Cancer
CPT-11 offers:CPT-11 offers:– Topoisomerase I inhibitionTopoisomerase I inhibition
– Consistent activity in colorectal cancer Consistent activity in colorectal cancer
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First-Line, Single-Agent CPT-11 TherapyFirst-Line, Single-Agent CPT-11 Therapy
CPT-11 offers similar activity to that of 5-FU/LVCPT-11 offers similar activity to that of 5-FU/LVCPT-11 offers similar activity to that of 5-FU/LVCPT-11 offers similar activity to that of 5-FU/LV
*Conti. *Conti. J Clin OncolJ Clin Oncol. 1996;14:709-715. . 1996;14:709-715. ^Pitot. ^Pitot. J Clin OncolJ Clin Oncol. 1997;15:2910-2919.. 1997;15:2910-2919.
Results of US phase II trials (N=72)Results of US phase II trials (N=72)
32%
26%
0%
10%
20%
30%
40%
Trial 1*(N=41)
Trial 2^(N=31)
Response RateResponse Rate
12.1 mo 11.8 mo
0
6
12
18
Trial 1*(N=41)
Trial 2^(N=31)
Survival (median)Survival (median)
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1010
RRAANNDDOOMMIIZZAATTIIOONN
CPT-11: 350 mg/mCPT-11: 350 mg/m22 every 3 weeks every 3 weeks
Best Supportive CareBest Supportive Care
PriorPrior5-FU5-FU
Second-Line CPT-11 Therapy Second-Line CPT-11 Therapy (V301)(V301)
Cunningham Cunningham et al. Lancetet al. Lancet. 1998; 352:1413-18... 1998; 352:1413-18..
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1111
00
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
00 33 66 99 1212 1515 1818 2121
MonthsMonths
Pro
bab
ilit
yP
rob
abil
ity
Second-Line SurvivalSecond-Line Survival(V301)(V301)
p=0.0001*p=0.0001*
* log-rank test* log-rank test
CPT-11CPT-11
BSCBSC
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1212
RRAANNDDOOMMIIZZAATTIIOONN
CPT-11: 350 mg/mCPT-11: 350 mg/m22 every 3 weeks every 3 weeks
Infusional 5-FU-based regimenInfusional 5-FU-based regimen
PriorPrior5-FU5-FU
Second-Line CPT-11 Therapy Second-Line CPT-11 Therapy (V302)(V302)
Rougier Rougier et al. Lancetet al. Lancet. 1998; 352:1407-12.. 1998; 352:1407-12.
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1313
00
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.0 1.0
00 33 66 99 1212 1515 1818 2121
MonthsMonths
Pro
bab
ilit
yP
rob
abil
ity
Second-Line SurvivalSecond-Line Survival(V302)(V302)
p=0.04*p=0.04*
* log-rank test* log-rank test
CPT-11CPT-11
InfusionalInfusional5-FU5-FU
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Different mechanism of action from 5-FUDifferent mechanism of action from 5-FU
Rationale for First-LineRationale for First-LineCPT-11 Combination TherapyCPT-11 Combination Therapy
Hypothesis: First-line combination of CPT-11 with Hypothesis: First-line combination of CPT-11 with 5-FU/LV will further improve tumor control and survival5-FU/LV will further improve tumor control and survival
Hypothesis: First-line combination of CPT-11 with Hypothesis: First-line combination of CPT-11 with 5-FU/LV will further improve tumor control and survival5-FU/LV will further improve tumor control and survival
Active as first-line, single-agent therapy Active as first-line, single-agent therapy
Extends survival when used as second-line therapyExtends survival when used as second-line therapy
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1515
*Saltz. *Saltz. J Clin OncolJ Clin Oncol. 1996;14:2959-2967. . 1996;14:2959-2967.
Weekly bolus regimenWeekly bolus regimen(Saltz -- Study 0007)(Saltz -- Study 0007)
Phase I Combination Dose-Finding Phase I Combination Dose-Finding and Pharmacokinetic Studiesand Pharmacokinetic Studies
Every-2-week infusional regimen Every-2-week infusional regimen (de Gramont -- Study F106)(de Gramont -- Study F106)
††Ducreux. Ducreux. J Clin OncolJ Clin Oncol. 1999;17:2901-2908.. 1999;17:2901-2908.
Weekly infusional regimenWeekly infusional regimen(AIO -- Study G101)(AIO -- Study G101)
‡‡Vanhoefer. Vanhoefer. J Clin OncolJ Clin Oncol. 1999;17:907-913. . 1999;17:907-913.
Addition of CPT-11 to existing schedules of 5-FU/LVAddition of CPT-11 to existing schedules of 5-FU/LV
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Pivotal Phase III TrialsPivotal Phase III Trials
Study Design and Conduct
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1717
Pivotal First-Line TrialsPivotal First-Line Trials
Two independent, phase III, prospective, randomized, controlled, international studies
CPT-11/Infusional 5-FU/LVCPT-11/Infusional 5-FU/LVvsvs
Infusional 5-FU/LVInfusional 5-FU/LV
AventisAventisStudy V303Study V303
CPT-11/Bolus 5-FU/LVCPT-11/Bolus 5-FU/LV vs vs
Bolus 5-FU/LVBolus 5-FU/LV vsvs
((CPT-11 alone)CPT-11 alone)
Pharmacia & UpjohnPharmacia & UpjohnStudy 0038Study 0038
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Entry CriteriaEntry Criteria(0038)(0038)
Histologically proven colorectal cancerHistologically proven colorectal cancer
Unresectable measurable metastasesUnresectable measurable metastases
Performance status 0, 1 or 2Performance status 0, 1 or 2
No prior chemotherapy for metastatic diseaseNo prior chemotherapy for metastatic disease
>12 months since completion of adjuvant 5-FU>12 months since completion of adjuvant 5-FU
No prior pelvic radiotherapy permittedNo prior pelvic radiotherapy permitted
Adequate hematologic, renal, and hepatic functionAdequate hematologic, renal, and hepatic function
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1919
Entry CriteriaEntry Criteria(V303)(V303)
Histologically proven colorectal cancerHistologically proven colorectal cancer
Unresectable measurable metastasesUnresectable measurable metastases
Performance status 0, 1 or 2Performance status 0, 1 or 2
No prior chemotherapy for metastatic diseaseNo prior chemotherapy for metastatic disease
>6>6 months since completion of adjuvant 5-FU months since completion of adjuvant 5-FU
Prior pelvic radiotherapy permittedPrior pelvic radiotherapy permitted
Adequate hematologic, renal, and hepatic functionAdequate hematologic, renal, and hepatic function
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2020
TreatmentTreatment(0038)(0038)
Treatment continued until tumor progression or Treatment continued until tumor progression or unacceptable toxicityunacceptable toxicity
Supportive care for all study arms included:Supportive care for all study arms included:– Atropine for the treatment of cholinergic symptomsAtropine for the treatment of cholinergic symptoms
– Loperamide for the treatment of late diarrhea Loperamide for the treatment of late diarrhea
– Antiemetics for the prophylaxis of nausea and vomitingAntiemetics for the prophylaxis of nausea and vomiting
Second-line, post-study chemotherapy permittedSecond-line, post-study chemotherapy permitted
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2121
TreatmentTreatment(V303)(V303)
Treatment continued until tumor progression or Treatment continued until tumor progression or unacceptable toxicityunacceptable toxicity
Supportive care for all study arms included:Supportive care for all study arms included:– Atropine for the treatment of cholinergic symptomsAtropine for the treatment of cholinergic symptoms
– Loperamide for the treatment of late diarrhea Loperamide for the treatment of late diarrhea
– Antiemetics for the prophylaxis of nausea and vomitingAntiemetics for the prophylaxis of nausea and vomiting
– Fluoroquinolone antibiotic for diarrhea in association with Fluoroquinolone antibiotic for diarrhea in association with grade 4 neutropenia or neutropenic fever
Second-line, post-study chemotherapy permittedSecond-line, post-study chemotherapy permitted
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2222
EndpointsEndpoints(0038)(0038)
Time to tumor progression Time to tumor progression (primary)(primary)
Tumor response rateTumor response rate
SurvivalSurvival
SafetySafety
Quality of life (EORTC QLQ-C30)Quality of life (EORTC QLQ-C30)
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2323
EndpointsEndpoints(V303)(V303)
Time to tumor progressionTime to tumor progression
Tumor response rate Tumor response rate (primary)(primary)
SurvivalSurvival
SafetySafety
Quality of life (EORTC QLQ-C30)Quality of life (EORTC QLQ-C30)
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2424
Patient EvaluationPatient Evaluation(0038)(0038)
On-study assessmentsOn-study assessments– Tumor measurements Tumor measurements (q 6 weeks x 4, then q 12 weeks)(q 6 weeks x 4, then q 12 weeks)
– Performance status, weight, Performance status, weight, quality of life, chemistries quality of life, chemistries (Day 1 of each cycle)(Day 1 of each cycle)
– Adverse events, CBCs Adverse events, CBCs (weekly)(weekly)
Follow-up Follow-up – Post-study chemotherapyPost-study chemotherapy
– SurvivalSurvival
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2525
Patient EvaluationPatient Evaluation(V303)(V303)
On-study assessmentsOn-study assessments– Tumor measurements Tumor measurements (q 6-7 weeks)(q 6-7 weeks)
– Performance status, weight, Performance status, weight, quality of life, chemistries quality of life, chemistries (Day 1 of each cycle)(Day 1 of each cycle)
– Adverse events, CBCs Adverse events, CBCs (weekly)(weekly)
Follow-up Follow-up – Post-study chemotherapyPost-study chemotherapy
– SurvivalSurvival
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2626
Sample Size CalculationSample Size Calculation(0038)(0038)
Primary endpoint assumptionsPrimary endpoint assumptions– 40% improvement in TTP40% improvement in TTP
Statistical testStatistical test = 0.05 and 1-= 0.05 and 1- = 0.85 = 0.85 – Unstratified log-rank Unstratified log-rank
Sample sizeSample size– 220 patients per treatment arm220 patients per treatment arm
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2727
Sample Size CalculationSample Size Calculation(V303)(V303)
Primary endpoint assumptionsPrimary endpoint assumptions– 40% improvement in response rate40% improvement in response rate
Statistical testsStatistical tests = 0.05 and 1-= 0.05 and 1- = 0.80 = 0.80 – Unstratified chi-squareUnstratified chi-square
Sample sizeSample size– 169 patients per treatment arm169 patients per treatment arm
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2828
RRAANNDDOOMMIIZZAATTIIOONN
Stratification:Stratification:
PS (0 vs 1, 2)PS (0 vs 1, 2)
Age Age (< 65 yr vs (< 65 yr vs >> 65 yr) 65 yr)
Time from initial Time from initial diagnosisdiagnosis(< 6 mo vs (< 6 mo vs >> 6 mo) 6 mo)
Prior adjuvant Prior adjuvant therapy therapy (yes vs no)(yes vs no) CPT-11:CPT-11: 125 mg/m125 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks
CPT-11:CPT-11: 125 mg/m125 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks5FU:5FU: 500 mg/m500 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks
LV:LV: 20 mg/m 20 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks
5FU:5FU: 425 mg/m425 mg/m22/d x 5 d, q 4 wks /d x 5 d, q 4 wks LV:LV: 20 mg/m 20 mg/m22/d x 5 d, q 4 wks/d x 5 d, q 4 wks
5-FU dose intensity=5-FU dose intensity=531531 mg/m mg/m22/wk/wk
5-FU dose intensity=5-FU dose intensity=333333 mg/m mg/m22/wk/wk
Treatment ArmsTreatment Arms(0038)(0038)
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2929
CPT-11:CPT-11: 80 mg/m 80 mg/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks5-FU:5-FU: 2.3 gm/m 2.3 gm/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks AIOAIO
LV:LV: 500 mg/m500 mg/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wksoror
CPT-11:CPT-11: 180 mg/m 180 mg/m22 d1 q 2 wks d1 q 2 wks5-FU:5-FU: 400 IV/600 CI mg/m400 IV/600 CI mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks de Gramontde Gramont
LV:LV: 200 mg/m200 mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks
5-FU:5-FU: 2.6 gm/m 2.6 gm/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks AIOAIOLV:LV: 500 mg/m500 mg/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks
oror5-FU:5-FU: 400 IV/600 CI mg/m400 IV/600 CI mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks de Gramontde Gramont
LV:LV: 200 mg/m200 mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks
RRAANNDDOOMMIIZZAATTIIOONN
Treatment ArmsTreatment Arms(V303)(V303)
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3030
Study Enrollment and Follow-UpStudy Enrollment and Follow-Up(0038)(0038)
Principal Investigator:Principal Investigator: Dr. Leonard SaltzDr. Leonard Saltz
Number of sites:Number of sites: 71 71 (Primarily North America)(Primarily North America)
Accrual period: Accrual period: May 1996 - May 1998May 1996 - May 1998
Survival cut-off: Survival cut-off: December 1999December 1999(19-month follow-up)(19-month follow-up)
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3131
Study Enrollment and Follow-UpStudy Enrollment and Follow-Up(V303)(V303)
Principal Investigator:Principal Investigator: Dr. Dr. Jean-YvesJean-Yves Douillard Douillard
Number of sites:Number of sites: 83 83 (Primarily Europe)(Primarily Europe)
Accrual period: Accrual period: May 1997 - February 1998May 1997 - February 1998
Survival cut-off: Survival cut-off: October 1999October 1999(20-month follow-up)(20-month follow-up)
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3232
Pivotal Phase III Trial ResultsPivotal Phase III Trial Results
Patient Characteristicsand Treatment Administration
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3333
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11
Intent-to-treat population Intent-to-treat population 231231 226226 226226
Never treated Never treated 4 4 8 8 4 4
Treated on another arm Treated on another arm 2 2 1 1 1 1
As-treated population As-treated population 225225 219219 223223
Patient EnrollmentPatient Enrollment(0038)(0038)
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3434
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV5-FU/LV
[AIO][AIO] [de Gramont][de Gramont] [AIO][AIO] [de Gramont][de Gramont]
RandomizedRandomized 199199 188188
Never treatedNever treated 11 11
Full-analysis populationFull-analysis population 198198 187187[53][53] [145] [145] [44][44] [143][143]
Treated on other armTreated on other arm 00 11
As-treated population As-treated population 199199 186 186 [54][54] [145] [145] [43][43] [143][143]
Patient EnrollmentPatient Enrollment(V303)(V303)
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3535
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Median age (yrs)Median age (yrs) 6262 6161 6161[range][range] [25-85][25-85] [19-85][19-85] [30-87][30-87]
Gender (% of pts)Gender (% of pts)
MM 6666 5555 6464 FF 3434 4545 3434
..
Performance status (% of pts)Performance status (% of pts) 00 3939 4242 4646
11 6161 5858 5454
DemographicsDemographics(0038)(0038)
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3636
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Median age (yrs)Median age (yrs) 6262 6161[range][range] [27-75][27-75] [25-75][25-75]
Gender (% of pts)Gender (% of pts)
MM 6767 5353 FF 3333 4747
..
Performance status (% of pts)Performance status (% of pts) 00 5252 5151
11 4848 4949
DemographicsDemographics(V303)(V303)
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3737
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Primary site (% of pts)Primary site (% of pts)ColonColon 8181 8585 8484RectumRectum 1717 1414 1515
Number of involvedNumber of involvedorgan sites (% of pts)organ sites (% of pts)
1 1 6464 6666 6262>>22 3636 3434 3838
Liver involvement (% of pts)Liver involvement (% of pts) 8282 8282 8383
Disease CharacteristicsDisease Characteristics(0038)(0038)
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3838
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Primary site (% of pts)Primary site (% of pts)ColonColon 5555 6565RectumRectum 4545 3636
Number of involvedNumber of involvedorgan sites (% of pts)organ sites (% of pts)
1 1 6262 6363>>22 3838 3737
Liver involvement (% of pts)Liver involvement (% of pts) 7777 8080
Disease CharacteristicsDisease Characteristics(V303)(V303)
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3939
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Median time from Median time from initial diagnosis (mo) initial diagnosis (mo) 1.9 1.9 1.71.7 1.8 1.8
[range][range] [0.1-161][0.1-161] [0.1-203][0.1-203] [0.1-186][0.1-186]
Prior adjuvant 5-FU Prior adjuvant 5-FU 1111 88 1010(% of pts)(% of pts)
Pelvic radiotherapy Pelvic radiotherapy 22 11 11(% of pts)(% of pts)
Disease HistoryDisease History(0038)(0038)
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4040
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Median time from Median time from initial diagnosis (mo) initial diagnosis (mo) 4.5 4.5 2.72.7
[range][range] [0.1-88][0.1-88] [0.1-104][0.1-104]
Prior adjuvant 5-FUPrior adjuvant 5-FU 2626 2424(% of pts)(% of pts)
RadiotherapyRadiotherapy 2020 1616(% of pts)(% of pts)
Disease HistoryDisease History(V303)(V303)
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4141
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Abnormal baseline value (% of pts)Abnormal baseline value (% of pts)
Hgb <11 g/dLHgb <11 g/dL 2626 2525 2626
WBC WBC 8x108x1099/L/L 5252 5353 5151
LDH >ULNLDH >ULN 6060 5656 5353
Bilirubin >ULNBilirubin >ULN 7 7 4 4 1010
CEA CEA 100 ng/mL100 ng/mL 4040 3939 3737
Baseline Laboratory AbnormalitiesBaseline Laboratory Abnormalities(0038)(0038)
*ULN = upper limit of normal*ULN = upper limit of normal
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4242
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Abnormal baseline value (% of pts)Abnormal baseline value (% of pts)
Hgb <11 g/dLHgb <11 g/dL 1616 2121
WBC WBC 8x108x1099/L/L 4747 3838
LDH >ULNLDH >ULN 4040 4444
Bilirubin >ULNBilirubin >ULN 7 7 7 7
CEA CEA 100 ng/mL100 ng/mL 3535 3232
Baseline Laboratory AbnormalitiesBaseline Laboratory Abnormalities(V303)(V303)
*ULN = upper limit of normal*ULN = upper limit of normal
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4343
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=225N=225 N=219N=219 N=223N=223
Median duration (mo)Median duration (mo) 5.55.5 4.14.1 3.93.9[range][range] [0.3-33][0.3-33] [0.4-22][0.4-22] [0.2-18][0.2-18]
..Median dose intensity (mg/mMedian dose intensity (mg/m22/wk) /wk) [Median relative dose intensity*][Median relative dose intensity*]
5-FU5-FU 236 236 [0.71][0.71] 457457 [0.86] [0.86] -- --
CPT-11CPT-11 60 60 [0.72][0.72] ---- 6262 [0.75] [0.75]
Treatment AdministrationTreatment Administration(0038)(0038)
*Ratio of actual dose intensity relative to planned dose intensity*Ratio of actual dose intensity relative to planned dose intensity
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4444
CPT-11/5-FU/LV CPT-11/5-FU/LV 5FU/LV 5FU/LV N=199N=199 N=186 N=186
AIOAIO de Gramontde Gramont AIOAIO de Gramontde Gramont
N=54N=54 N=145N=145 N=43N=43 N=143N=143
Median duration (mo) Median duration (mo) 5.55.5 5.75.7 4.84.8 4.24.2 [range][range] [0.5-14.8][0.5-14.8] [0.5-15.7] [0.5-15.7] [0.2-10.6] [0.2-10.6] [0.5-11.5][0.5-11.5]
Median relative dose intensity *Median relative dose intensity *
CPT-11CPT-11 0.820.82 0.930.93 ---- ----
5-FU 5-FU 0.810.81 0.920.92 0.900.90 0.960.96
Treatment AdministrationTreatment Administration(V303)(V303)
*Ratio of actual dose intensity relative to planned dose intensity*Ratio of actual dose intensity relative to planned dose intensity
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4545
Pivotal Phase III Trial ResultsPivotal Phase III Trial Results
Efficacy and Safety
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4646
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV5-FU/LV CPT-11CPT-11N=(231,198)N=(231,198) N=(226,187)N=(226,187) N=226N=226
Study 0038Study 0038 39%39% 21%21% 18%18%
Study V303Study V303 35% 35% 22%22%
Confirmed Response RatesConfirmed Response Rates (0038,V303) (0038,V303)
Responses confirmed Responses confirmed 4 weeks after initial objective response4 weeks after initial objective response*Chi-square test*Chi-square test
p<0.005*p<0.005*
p<0.0001*p<0.0001*
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4747
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV5-FU/LV CPT-11CPT-11N=(231,198)N=(231,198) N=(226,187)N=(226,187) N=226N=226
Median (0038) Median (0038) 7.0 mo7.0 mo 4.3 mo4.3 mo 4.2 mo4.2 mo
Median (V303) Median (V303) 6.7 mo 6.7 mo 4.4 mo4.4 mo
*Log-rank test*Log-rank test
Time to Tumor ProgressionTime to Tumor Progression (0038,V303) (0038,V303)
p=0.004*p=0.004*
p<0.001*p<0.001*
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4848
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
Months
Pro
bab
ilit
y
CPT-11/5-FU/LV (N=231)
5-FU/LV (N=226)
* log-rank test* log-rank test
p=0.004*
Time to Tumor ProgressionTime to Tumor Progression(0038)(0038)
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4949
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15
Months
Pro
bab
ility
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
Time to Tumor Progression Time to Tumor Progression (V303)(V303)
p<0.001*
* log-rank test* log-rank test
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5050
Hazard RatioHazard Ratio FactorFactor Value Value [95% CI][95% CI] p-valuep-value
LDHLDH UNL vs >UNL UNL vs >UNL 0.600.60 0.00010.0001[0.47-0.76][0.47-0.76]
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.63 0.63 0.0001 0.0001 [0.50–0.80][0.50–0.80]
PSPS 0 vs 0 vs 1 1 0.74 0.74 0.0088 0.0088 [0.59–0.93][0.59–0.93]
BilirubinBilirubin UNL vs >UNL UNL vs >UNL 0.56 0.56 0.01320.0132[0.35–0.89][0.35–0.89]
HemoglobinHemoglobin < 11 vs < 11 vs 11 g/dL 11 g/dL 0.740.74 0.01570.0157[0.58–0.95][0.58–0.95]
AgeAge 65 vs <65 years65 vs <65 years 0.78 0.78 0.03150.0315[0.63–0.98][0.63–0.98]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.640.64 0.00010.0001 vs 5-FU/LVvs 5-FU/LV [0.51–0.79][0.51–0.79]
*ULN=upper limit of normal*ULN=upper limit of normal
Cox Regression Analysis: TTPCox Regression Analysis: TTP(0038)(0038)
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5151
Hazard RatioHazard Ratio FactorFactor Value Value [95% CI][95% CI] p-valuep-value
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.73 0.73 0.0001 0.0001 [0.57–0.94][0.57–0.94]
LDHLDH UNL vs >UNL UNL vs >UNL 0.640.64 0.00120.0012[0.48-0.84][0.48-0.84]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.590.59 0.00010.0001 vs 5-FU/LVvs 5-FU/LV [0.46–0.76][0.46–0.76]
Cox Regression Analysis: TTPCox Regression Analysis: TTP(V303)(V303)
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5252
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV5-FU/LV CPT-11CPT-11N=(231,198)N=(231,198) N=(226,187)N=(226,187) N=226N=226
Median (0038)Median (0038) 14.8 mo14.8 mo 12.6 mo12.6 mo 12.0 mo12.0 mo
Median (V303)Median (V303) 17.4 mo 17.4 mo 14.1 mo14.1 mo
Survival Survival (0038,V303)(0038,V303)
*Log-rank test*Log-rank test
p=0.042*p=0.042*
p=0.032*p=0.032*
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5353
0.0
0.10.2
0.3
0.40.5
0.6
0.7
0.80.9
1.0
0 6 12 18 24 30 36 42
Months
CPT-11/5-FU/LV (N=231)
5-FU/LV (N=226)
SurvivalSurvival(0038)(0038)
p=0.042*
Pro
bab
ilit
y
* log-rank test* log-rank test
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5454
Survival Survival (V303)(V303)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30
Months
Pro
bab
ilit
y
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
p=0.032*
* log-rank test* log-rank test
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5555
Hazard RatioHazard Ratio FactorFactor Value Value [95% CI][95% CI] p-valuep-value
LDHLDH UNL vs >UNL UNL vs >UNL 0.470.47 0.00010.0001[0.37-0.60][0.37-0.60]
PSPS 0 vs 0 vs 1 1 0.57 0.57 0.0001 0.0001 [0.45–0.71][0.45–0.71]
WBCWBC <8 vs <8 vs 8 x 108 x 1099/L /L 0.640.64 0.00010.0001[0.51–0.80][0.51–0.80]
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.67 0.67 0.0004 0.0004 [0.54–0.84][0.54–0.84]
BilirubinBilirubin UNL vs >UNL UNL vs >UNL 0.55 0.55 0.00510.0051[0.35–0.86][0.35–0.86]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.800.80 0.03720.0372 vs 5-FU/LVvs 5-FU/LV [0.64–0.99][0.64–0.99]
Cox Regression Analysis: SurvivalCox Regression Analysis: Survival(0038)(0038)
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5656
Hazard RatioHazard RatioFactorFactor ValueValue [95% CI][95% CI] p-valuep-value
LDHLDH UNL vs >UNL UNL vs >UNL 0.550.55 0.00010.0001[0.42-0.72][0.42-0.72]
PSPS 0 vs 0 vs 1 1 0.52 0.52 0.0001 0.0001 [0.41–0.67][0.41–0.67]
Time fromTime from 1 vs < 1 mo 1 vs < 1 mo .63.63 0.00050.0005Metastatic DxMetastatic Dx [0.49-0.82][0.49-0.82]
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.73 0.73 0.0127 0.0127 [0.57–0.94][0.57–0.94]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.770.77 0.03650.0365 [vs 5-FU/LV][vs 5-FU/LV] [0.61–0.98][0.61–0.98]
Cox Regression Analysis: SurvivalCox Regression Analysis: Survival(V303)(V303)
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5757
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=205N=205 N=203N=203 N=195N=195
Patients with any Patients with any 52%52% 70%70% 79%79%post-study therapypost-study therapy
CPT-11-basedCPT-11-based 1% 1% 38%38% 3% 3%CPT-11+5-FU-basedCPT-11+5-FU-based 13%13% 18%18% 9% 9%5-FU-based5-FU-based 30%30% 10%10% 64% 64%Other therapyOther therapy 8% 8% 4% 4% 3% 3%
Patients not treatedPatients not treated 48%48% 30%30% 21%21%
Post-Study TherapyPost-Study Therapy(0038)(0038)
56%56%
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5858
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=167N=167 N=171N=171
Patients with any Patients with any 49%49% 65%65%post-study therapypost-study therapy
CPT-11-basedCPT-11-based 2% 2% 28%28%CPT-11+5-FU-basedCPT-11+5-FU-based 4% 4% 6% 6% 5-FU-based5-FU-based 32%32% 21%21%Other therapyOther therapy 11%11% 10%10%
Patients not treatedPatients not treated 51%51% 35%35%
Post-Study TherapyPost-Study Therapy(V303)(V303)
34%34%
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5959
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11Event (% of pts) Event (% of pts) N=225N=225 N=219N=219 N=223N=223
Diarrhea, grade 3/4Diarrhea, grade 3/4 2323 1313 3131
Grade 3Grade 3 1515 6 6 1818
Grade 4Grade 4 8 8 7 7 1313
Vomiting, grade 3/4Vomiting, grade 3/4 1010 4 4 1212
Mucositis, grade 3/4Mucositis, grade 3/4 2 2 1717 2 2
Neutropenia, grade 4Neutropenia, grade 4 2424 4343 1212
Neutropenic feverNeutropenic fever 7 7 1515 6 6
Neutropenic infectionNeutropenic infection 2 2 0 0 2 2
DiscontinuationsDiscontinuations 8 8 6 6 1212
Drug-related deathsDrug-related deaths 0.9 0.9 1.41.4 0.90.9
Adverse EventsAdverse Events(0038)(0038)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV Event (% of pts) Event (% of pts) N=199N=199 N=186N=186
Diarrhea, grade 3/4Diarrhea, grade 3/4 2323 1111
Grade 3Grade 3 1717 7 7
Grade 4Grade 4 6 6 4 4
Vomiting, grade 3/4Vomiting, grade 3/4 6 6 3 3
Mucositis, grade 3/4Mucositis, grade 3/4 3 3 3 3
Neutropenia, grade 4Neutropenia, grade 4 9 9 1 1
Neutropenic feverNeutropenic fever 5 5 1 1
Neutropenic infectionNeutropenic infection 2 2 0 0
DiscontinuationsDiscontinuations 9 9 3 3
Drug-related deathsDrug-related deaths 0.5 0.5 0 0
Adverse EventsAdverse Events(V303)(V303)
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Quality of Life
Pivotal Phase III Trial ResultsPivotal Phase III Trial Results
Study 0038 primary endpointsStudy 0038 primary endpoints– Global health statusGlobal health status
– Role functioningRole functioning
– PainPain
Study V303 primary endpointStudy V303 primary endpoint– Global health statusGlobal health status
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Global Health Status Subscale
-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
Weeks
BetterBetter
WorseWorse
Me
an
Ch
an
ge
(s
e)
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(0038)(0038)
CPT-11/5-FU/LV
5-FU/LV
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-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(0038)(0038)
Weeks
BetterBetter
WorseWorse
Me
an
Ch
an
ge
(s
e)
Role Functioning Subscale
CPT-11/5-FU/LV
5-FU/LV
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-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
Weeks
WorseWorse
BetterBetter
Me
an
Ch
an
ge
(s
e)
Pain Subscale
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(0038)(0038)
CPT-11/5-FU/LV
5-FU/LV
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Global Health Status Subscale
-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
Weeks
BetterBetter
WorseWorse
Me
an
Ch
an
ge
(s
e)
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(V303)(V303)
CPT-11/5-FU/LV
5-FU/LV
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Summary and ConclusionsSummary and Conclusions
Two independent, phase III, prospective, randomized,
controlled, multinational studies
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Significantly lengthens time to tumor progressionSignificantly lengthens time to tumor progression
Efficacy SummaryEfficacy Summary
Significantly improves response rateSignificantly improves response rate
First-line combination CPT-11/5-FU/LV
Significantly prolongs survival Significantly prolongs survival
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Safety SummarySafety Summary
Predictable and manageable side effect profilePredictable and manageable side effect profile
First-line combination CPT-11/5-FU/LV
Similar incidence of grade 4 diarrhea relative Similar incidence of grade 4 diarrhea relative to 5-FU/LVto 5-FU/LV
Low rates of grade 3/4 vomiting, mucositis, Low rates of grade 3/4 vomiting, mucositis, neutropenia, and febrile neutropenianeutropenia, and febrile neutropenia
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Quality of Life SummaryQuality of Life Summary
Prolongs life without compromising quality of lifeProlongs life without compromising quality of life
First-line combination CPT-11/5-FU/LV
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ConclusionConclusion
CPT-11-based combination therapy sets CPT-11-based combination therapy sets a new standard in the first-line treatment of metastatic colorectal cancer
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Proposed New IndicationProposed New Indication
CPT-11 should be indicated as a component of first-line therapy for patients with metastatic carcinoma of the colon or rectum
Recommended CPT-11/5-FU/LV regimens:
– Saltz
– de Gramont
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Q & AQ & A