isagani m. chico, md medical officer
DESCRIPTION
A POST-MARKETING EVALUATION OF SAFETY CAMPTOSAR + 5-FU/LV FOR FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER. ISAGANI M. CHICO, MD Medical Officer. EARLY DEATHS IN IRINOTECAN+5FU/LV. PLAN OF ACTION. EVALUATE DEATHS. REANALYZE LICENSING TRIALS. ONGOING TRIALS. - PowerPoint PPT PresentationTRANSCRIPT
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