1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar Pharmacia...

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

22

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

33

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

44

Background

55

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.

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

77

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)


11.3 mo 12.1 mo

0

6

12

18

5-FUBolus

(N=612)

5-FUInfusion(N=607)


88

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

99

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)


12.1 mo 11.8 mo

0

6

12

18

Trial 1*(N=41)

Trial 2^(N=31)


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..

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

1212


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.

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*


CPT-11CPT-11

InfusionalInfusional5-FU5-FU

1414

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

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

1616

Pivotal Phase III TrialsPivotal Phase III Trials

Study Design and Conduct

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

1818

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

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

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

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

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)

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)

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

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

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

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

2828


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)

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


Treatment ArmsTreatment Arms(V303)(V303)

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)

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)

3232

Pivotal Phase III Trial ResultsPivotal Phase III Trial Results

Patient Characteristicsand Treatment Administration

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)

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)

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)

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)

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)

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)

3939


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)

4040


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)

4141


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

4242


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

4343


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

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

4545


Efficacy and Safety

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*

4747


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*

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)


p=0.004*

Time to Tumor ProgressionTime to Tumor Progression(0038)(0038)

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*


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)

5151





Cox Regression Analysis: TTPCox Regression Analysis: TTP(V303)(V303)

5252


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*

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


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*


5555



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]


BilirubinBilirubin UNL vs >UNL UNL vs >UNL 0.55 0.55 0.00510.0051[0.35–0.86][0.35–0.86]


Cox Regression Analysis: SurvivalCox Regression Analysis: Survival(0038)(0038)

5656

Hazard RatioHazard RatioFactorFactor ValueValue [95% CI][95% CI] p-valuep-value


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]


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)

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%

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%

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)

6060

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)

6161

Quality of Life


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

6262

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

6363

-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)

Role Functioning Subscale

CPT-11/5-FU/LV

5-FU/LV

6464

-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


CPT-11/5-FU/LV

5-FU/LV

6565

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

6666

Summary and ConclusionsSummary and Conclusions

Two independent, phase III, prospective, randomized,

controlled, multinational studies

6767

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

6868

Safety SummarySafety Summary

Predictable and manageable side effect profilePredictable and manageable side effect profile


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

6969

Quality of Life SummaryQuality of Life Summary

Prolongs life without compromising quality of lifeProlongs life without compromising quality of life


7070

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

7171

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

7272

Q & AQ & A

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1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar Pharmacia...

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