isagani m. chico, md medical officer

A POST-A POST-MARKETING MARKETING

EVALUATION OF EVALUATION OF SAFETYSAFETY

CAMPTOSAR + 5-FU/LV CAMPTOSAR + 5-FU/LV FORFOR

FIRST-LINE TREATMENT FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCEROF METASTATIC COLORECTAL CANCER

ISAGANI M. CHICO, MD

Medical Officer

EARLY DEATHS EARLY DEATHS IN IN

IRINOTECAN+5FUIRINOTECAN+5FU/LV /LV

EVALUATE DEATHS

ONGOING TRIALS

REANALYZE LICENSING TRIALS

PLAN OF ACTION

REGULATORY ACTION

DEFINITION OF DEFINITION OF REGIMENSREGIMENS

RegimenDrugs Cycle Schedule

BOLUS REGIMENS

Saltz I + FLWeekly BOLUS for 4 weeksevery 6 weeks

Mayo Clinic FLDaily BOLUS for 5 daysevery 4 weeks

Roswell Park FLWeekly BOLUS for 6 weeksevery 8 weeks

CONTINUOUS INFUSION REGIMENS

Douillard I + FLCONTINUOUS IV x 2 daysEvery 2 weeks

de GramontFL CONTINUOUS IV x 2 days

Every 2 weeks

PLAN OF ACTION PLAN OF ACTION

EVALUATE DEATHS

ONGOING TRIALS

REANALYZE LICENSINGTRIALS

REGULATORY ACTION

“Independent Panel”PharmaciaFDA

POST MARKETING EVENTS

PLAN OF ACTION PLAN OF ACTION

EVALUATE DEATHS

“Independent Panel” Pharmacia FDA

ONGOING TRIALS

REANALYZE LICENSING TRIALS

REGULATORY ACTION

PharmaciaFDA

POST MARKETING EVENTS

PLAN OF ACTION PLAN OF ACTION

EVALUATE DEATHS

“Independent Panel” Pharmacia FDA

ONGOING TRIALS

REANALYZE LICENSING TRIALS

Pharmacia FDA

REGULATORY ACTION

Pharmacia

POST MARKETING EVENTS

FDA REVIEW FDA REVIEW

1. Early Deaths from NCCTG and CALGB

2. Early Deaths from Licensing Trials

3. Safety in the Licensing Trials

EARLY DEATHS EARLY DEATHS NCCTG 9741 AND CALGB 89803NCCTG 9741 AND CALGB 89803

DEMOGRAPHICS(n=29)

AGEMedian<65>65

691217

GENDERMF

1217

KPS0-12unknown

26 2 1

MEDICALHISTORY

CardiovascularRenalEndocrine

11 2 3

ENTRYVIOLATIONS

3 weeks from surgery (1)Unresolved GI Infection (1)Baseline Creatinine 1.6 (1)Performance Status 3 (1)

SyndromesNCCTGn=(13)

CALGB(n=16)

TOTAL(n=29)

Gastrointestinal

Hematologic/Infections

GI + Heme/Infections

Vascular Only

Vascular +Other

1

2

7(54%)

2

3

0

1

11(69%)

3

4

1

3

18(62%)

5

7

Median Time to Gr. 3 12 days 20 days 15 days

Median Time to Death 26 days 29 days 28 days

EARLY DEATHS EARLY DEATHS NCCTG 9741 AND CALGB 89803NCCTG 9741 AND CALGB 89803

DEATH ANALYSIS DEATH ANALYSIS MethodsMethods

Coop Group 60 DAYS (EARLY)

Other Trials 60 DAYS (EARLY) --

Licensing Trials

Label

30 DAYS FROM LAST TREATMENT30 DAYS FROM LAST TREATMENT(ALL CYCLES)(ALL CYCLES)

60 DAYS FROM FIRST TREATMENT (EARLY)

Small time window Acute toxicity Interim look at a subset of

patients Subjective determination of

causality

30 DAYS FROM LAST TREATMENT (ALL CYCLES)

All cycles considered

Overall toxicity

Complete and mature data Temporal relationship implies

role in death with no judgment of causality

DEATH ANALYSIS DEATH ANALYSIS DefinitionsDefinitions

EARLY DEATHS EARLY DEATHS Metastatic DiseaseMetastatic Disease

COOPERATIVEGROUPS

LICENSING TRIALS

N9741 0038 V303DEATH

ALL CAUSES

Bolus IFL(289)

Ox-FL(277)

Ox-I(275)

Bolus IFL(225)

MayoFL(219)

ContinuousIFL

(145)

DeGramont(143)

60 Days from StartTreatment

1.8% 1.8%

30 Days from LastTreatment

NA NA NA 7% 3%

6.7% 7.3% 2.0% 2.1%6.7% 7.3% 2.0% 2.1%4.8%4.8%

9% 4%9% 4%

ADJUVANTSTUDY LICENSING TRIALS

C89803 0038 V303DEATH

ALL CAUSESBolus IFL

(635)RP-FL(628)

Bolus IFL(225)

MayoFL(219)

Continuous IFL(145)

DeGramont(143)

60 Days fromStart Treatment

0.8% 6.7% 7.3% 2.0% 2.1%

30 Days fromLast Treatment

NA NA 9% 7% 4% 3%

EARLY DEATHS EARLY DEATHS Adjuvant TreatmentAdjuvant Treatment

2.2%2.2%

LICENSING TRIALS LICENSING TRIALS

• Safety profile of the approved Continuous Infusion IFL could be reassessed

• Explore signals from early deaths in the cooperative group trials

• Complete and mature database

LICENSING TRIALS: LICENSING TRIALS: EARLY DEATHS EARLY DEATHS

Patient CharacteristicsPatient Characteristics

Deaths within 60 Days (Bolus IFL Regimen)

Patient CharacteristicsCoop Group Trials

(N9741 and C89803)n=29

Licensing Trial

(0038)n=15

Age (median) 69 61

Performance Status

0-12

262

123

GenderMF

1217

114

LICENSING TRIALS LICENSING TRIALS Patient CharacteristicsPatient Characteristics

Patient Characteristic

Study 0038Saltz

Arm BN = 231

Study V303Douillard +AIO

Arm AN = 198

Performance Status0 89 (38.5%) 102 (51.5%)

1 106 (45.9%) 83 (41.9%)

2 35 (15.2%) 13 (6.6%)Site of Primary Tumor

Colon 188 (81.4%) 108 (54.5%)Rectum 38 (16.5%) 90 (45.5%)

Prior Adjuvant 5-FUNo 206 (89.2%) 147 (74.2%)Yes 25 (10.8%) 51 (25.8%)

Any PriorRadiotherapy 7 (3.0%) 40 20.2%

LICENSING TRIALSLICENSING TRIALSPerformance StatusPerformance Status

Licensing Trial 0038

Bolus IFL(n=225)

5FU/LV(n=219)DEATHS

PS 0-1(n=192)

PS 2(n=33)

PS 0-1(n=190)

PS 2(n=29)

60 Days from Start ofTreatment (%)

7 (4) 8 (24) 9 (5) 7 (24)

30 Days From Start ofTreatment (%)

11 (6) 10 (30) 8 (4) 7 (25)

LICENSING TRIALSLICENSING TRIALSPerformance StatusPerformance Status

0038(Bolus)

V303(Continuous

Infusion)

Baseline PS PS = 0/1 PS = 2 PS = 0/1 PS = 2

Irinotecan/5-FU/LV N=192 N = 35 N = 133 N = 12

Median TTP (months) 5.8 1.6 4.3 5.7

Median Survival (months) 14.6 3.9 12.5 11.6

5-FU/LV N= 190 N = 29 N = 132 N =11

Median TTP (months) 4.2 1.9 3.0 1.6

Median Survival (months) 13.5 6.1 12.4 4.8

SPONSOR’S SPONSOR’S PROPOSED LABEL PROPOSED LABEL

CHANGECHANGEPopulations at RiskPopulations at Risk

Exclude treatment of patients with PS 3 and 4

QUESTIONQUESTIONPOPULATIONS AT RISK

Should the indication exclude:

PS 3 or PS 2?

Age 65?

Others?

LICENSING TRIALS: LICENSING TRIALS: Safety ProfileSafety Profile

Early Deaths (Bolus IFL)

Coop Group Trials

(N9741 and C89803)n=29

Licensing Trial

(0038)n=15

Days from Start ofTreatment to Death

28 28

SYNDROMES

Gastrointestinal 1 3

Hematologic/Infectious 3 3

GI + Heme/Infectious 18 (62%) 9 (60%)

SPONSOR’S SPONSOR’S PROPOSED LABEL PROPOSED LABEL

CHANGECHANGESupportive Care and MonitoringSupportive Care and Monitoring

Fluoroquinolone 7 day course for diarrhea persistent >24 hours, fever accompanying diarrhea, and for ANC <500

Antibiotic support for patients with severe diarrhea if they develop ileus, fever, or severe neutropenia

GCSF for Grade 2 neutropenia

Weekly assessment during the first cycle of therapy

CBC/Diff within 48 hours prior to treatment

For Grade 2 Diarrhea or Neutropenia = HOLD, No dose reduction

For Grade 3 Diarrhea = Hold until Grade 1, then resume at 1 dose level reduction

Patients must be diarrhea-free for 24 hrs prior to retreatment,

SPONSOR’S SPONSOR’S PROPOSED LABEL PROPOSED LABEL

CHANGECHANGE Dose Modifications Dose Modifications

MODIFICATIONS MODIFICATIONS ADOPTED ADOPTED BY NCCTG BY NCCTG

Changes in Dose Modification For Grade 2 diarrhea or neutropenia = HOLD and reduce one dose

level

For Grade 3 diarrhea or neutropenia = HOLD, Reduce two dose levels.

Lower Starting Dose of Irinotecan and 5-FU• Camptosar 125 mg/m2 to 100 mg/m2

• 5-FU from 500 mg/m2 to 400 mg/m2

CHOICE OF CONTROL CHOICE OF CONTROL ARM ARM

BOLUS IFL vs. CONTINUOUS INFUSION IFL?

• Continuous Infusion IFL in future studiesContinuous Infusion IFL in future studies

LICENSING TRIALS: LICENSING TRIALS: Safety ProfileSafety Profile

% Receiving Full Dose in Bolus IFL Arm, Study 0038

Cycle (C)/Week (W) C1W1 C1W2 C1W3 C1W4 C2W1 C3W1

Patients at Risk (N) 225 223 209 200 184 156Irinotecan (%) 99 87 60 42 46 425-FU (%) 99 86 60 42 47 40

% Receiving Full Dose in Continuous Infusion Arm, Study V303

Cycle (C)/Week (W) C1W1 C1W3 C1W5 C2W1

Patients at Risk (N) 145 140 136 125Irinotecan (%) 96 89 87 865-FU (%) 93 88 85 83

LICENSING TRIALS:LICENSING TRIALS:Overall ToxicityOverall Toxicity

Risk for ToxicityPatientCharacteristics

0038 (Saltz)n=225

V303 (Douillard)n=145

Neutropenic Fever or Infection

First CycleAll Cycles

29 (13%)36 (16%)

5 (3.5%)8 (5.5%)

Discontinuation due to AE’s

First CycleAll Cycles

7 (3%)17 (8%)

4 (3%)9 (6%)

Hospitalizations

First CycleAll Cycles

69 (31%)113 (50%)

34 (23.5%)59 (41%)

INFUSION vs. INFUSION vs. BOLUS 5-FUBOLUS 5-FU

Trial 5-FU (mg/m2) CIVI 5-FU (mg/m2) Bolus # Pts.

ECOG 300 /day continuously 500 d1-d5, then 600 q 7 days 324

NCIC 350/day, d1-d15 q 28 days 400-450 d1-5, q 28 days 185

SWOG 300/day, d1-d28 q 35 days 500 d1-d5, q 35 days 181

MAOP 300/day continuously 500 d1-d5, q 35 days 173

France 750 d1-d7, q 21 days 500 d1-d5, q 28 days 155

SWOG 300/day, d1-d28 q 35 days +LV 20 IV q7 days

425 +LV 20, d1-d5 q28 x 2,then q 35 days

175

INFUSION vs. INFUSION vs. BOLUS 5-FUBOLUS 5-FU

5-FU CIVI 5-FU Bolus

Response 22% 14% OR= 0.55

(95% CI=0.41-0.75)

Survival 12.1 months 11.3 months HR=0.88 p=0.04

Toxicity

Gr 3+4 hematologic 4% 31% P<10-16

Other non-heme 14% 13% --

IRINOTECAN or 5-IRINOTECAN or 5-FU ??FU ??

LICENSING TRIALS

0038 V303DEATH

ALL CAUSESBolus IFL

(225)MayoFL

(219)Continuous IFL

(145)DeGramont

(143)

60 Days fromStart Treatment

6.3% 7.3% 2.0% 2.1%

POTENTIAL ACTIONPOTENTIAL ACTION

NO CHANGE

POTENTIAL ACTIONPOTENTIAL ACTION

MINOR CHANGES

POTENTIAL ACTIONPOTENTIAL ACTION

MAJOR CHANGES

• Requiring randomized Requiring randomized controlled trials controlled trials

POTENTIAL ACTIONPOTENTIAL ACTION

REMOVAL OF BOLUS IFL FROM THE LABEL

• While studies are ongoingWhile studies are ongoing

• Continuous infusion IFL remains Continuous infusion IFL remains in the label in the label