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Development of New Drugs: Lessons from Clinical Trials Paul A. Meyers, MD Vice-Chair, Pediatrics Memorial Sloan-Kettering Professor of Pediatrics Weill Cornell Medical College
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Development of New Drugs:Lessons from Clinical Trials
Paul A. Meyers, MDVice-Chair, Pediatrics
Memorial Sloan-KetteringProfessor of Pediatrics
Weill Cornell Medical College
Paul A. Meyers, MDVice-Chair, Pediatrics
Memorial Sloan-KetteringProfessor of Pediatrics
Weill Cornell Medical College
Combining biological agents with chemotherapy
Phase 1 Safety profile Pharmacology Active dose/MTD
Phase 2 Preliminary efficacy Design considerations
Phase 3 Design considerations Choice of outcome variable Statistical considerations Duration of followup
Benefit-risk ratio & regulatory considerations
Phase 1 Safety profile Pharmacology Active dose/MTD
Phase 2 Preliminary efficacy Design considerations
Phase 3 Design considerations Choice of outcome variable Statistical considerations Duration of followup
Benefit-risk ratio & regulatory considerations
Phase 1
• First-in-man
• Few anti-cancer agents are tested in healthy volunteers
• Pharmacokinetics, pharmacodynamics,
metabolism
• Toxicity/ active dose/MTD
• First-in-man
• Few anti-cancer agents are tested in healthy volunteers
• Pharmacokinetics, pharmacodynamics,
metabolism
• Toxicity/ active dose/MTD
Phase 1: Biologics/BRMs
•Studies in patients with a variety of cancers, usually late stage. • Clinical activity may be rare in patients with bulky disease
•Pharmacology• Non-linear dose/response (threshold doses, tachyphylaxis)• Biologic activity – passive/active
•Studies in patients with a variety of cancers, usually late stage. • Clinical activity may be rare in patients with bulky disease
•Pharmacology• Non-linear dose/response (threshold doses, tachyphylaxis)• Biologic activity – passive/active
Phase 1: MTP
• Phase 1 studies in patients with late stage cancers
• Anecdotal responses
• Optimal biologic activity .5-2mg/m2
• MTD (<grade 3 events) 4-6mg/m2
• Phase 1 studies in patients with late stage cancers
• Anecdotal responses
• Optimal biologic activity .5-2mg/m2
• MTD (<grade 3 events) 4-6mg/m2
Phase 1: IGF1R Inhibitors
• Few dose limiting toxicities (antibodies) – dosing based on biomarkers?
• Clinical activity
• Few dose limiting toxicities (antibodies) – dosing based on biomarkers?
• Clinical activity
Phase 2
• Larger group of patients (usually 50-200)
• Obtain evidence of efficacy in target indication
• Extend safety information • Obtain information needed to plan
randomized efficacy studies
• Larger group of patients (usually 50-200)
• Obtain evidence of efficacy in target indication
• Extend safety information • Obtain information needed to plan
randomized efficacy studies
Phase 2: Biologics/BRMs
• Bulk disease vs minimal residual disease• Animal models
• Mechanism of action (passive/active)• Activation of host immune system
• Synergy/antagonism with chemotherapy• Preclinical data
• Bulk disease vs minimal residual disease• Animal models
• Mechanism of action (passive/active)• Activation of host immune system
• Synergy/antagonism with chemotherapy• Preclinical data
Phase 2: MTP in osteosarcoma
Impact of data from canine OS
Expectation of benefit in mrd
In vivo evidence of anti-tumor activity
Impact of data from canine OS
Expectation of benefit in mrd
In vivo evidence of anti-tumor activity
Phase 2: MTP and osteosarcoma
Planning for Phase 3
With/without chemotherapy Proposed mechanism of action
a) activation of macrophages
b) fas/fas-ligand interaction• Administer with chemotherapy
• Role of adjuvant phase 2 design
Planning for Phase 3
With/without chemotherapy Proposed mechanism of action
a) activation of macrophages
b) fas/fas-ligand interaction• Administer with chemotherapy
• Role of adjuvant phase 2 design
Phase 2: IGF1R inhibition in sarcoma
• Single agent vs chemo combination
• Outcome: objective response, PFS, survival
• Randomized trial or historical control
• Use of phase 2 data impact design
• Single agent vs chemo combination
• Outcome: objective response, PFS, survival
• Randomized trial or historical control
• Use of phase 2 data impact design
Phase 3
• Confirmation studies: prove that the
promising effects seen in Phase II are real
(usually 100-1,000 people)
• Safety
• Confirmation studies: prove that the
promising effects seen in Phase II are real
(usually 100-1,000 people)
• Safety
Phase 3: Biologics/BRMs
• Design considerations• In combination with other agents• Timing of introduction• Timing of randomization
• Design considerations• In combination with other agents• Timing of introduction• Timing of randomization
Phase 3: Design Considerations MTP and Osteosarcoma
Timing of introduction
Phase I/II trials suggest use in mrd
Introduce after surgical resection of
clinically detectable disease
Timing of introduction
Phase I/II trials suggest use in mrd
Introduce after surgical resection of
clinically detectable disease
• Timing of introduction
• Delayed introduction of new agent will be ineffective
Failure in osteosarcoma: appearance of metastatic
nodules
Reflects events months earlier
• Timing of randomization
• Timing of introduction
• Delayed introduction of new agent will be ineffective
Failure in osteosarcoma: appearance of metastatic
nodules
Reflects events months earlier
• Timing of randomization
Phase 3: Design Considerations MTP and Osteosarcoma
Survival and DFS2007 ITT Data
Years
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
SurvivalDFS
Phase 3: Design Considerations Osteosarcoma
Survival
DFS
Phase 3 Study Design
A Cisplatin
DoxorubicinHDMTX
BIfosfamide
DoxorubicinHDMTX
INDUCTION INDUCTION
Cisplatin, Ifosfamide, Doxorubicin, HDMTXCisplatin, Ifosfamide, Doxorubicin, HDMTX
2020 36362727WeeksWeeks
Cisplatin, Doxorubicin, HDMTXCisplatin, Doxorubicin, HDMTX
MAINTENANCE MAINTENANCE
A
B
Cisplatin, Doxorubicin, HDMTX, Cisplatin, Doxorubicin, HDMTX, MTPMTP
Cisplatin, Ifosfamide,Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Doxorubicin, HDMTX, MTPMTP
A+
B+
DEFINITIVE
SURGERY
DEFINITIVE
SURGERY
R Introduction of MTP
Phase 3: Design ConsiderationsIGF R Inhibitors
Timing of introduction
Phase II trials show objective responses
Synergy with chemotherapy
Timing of introduction
Phase II trials show objective responses
Synergy with chemotherapy
Phase 3: Biologics/BRMs
• Statistical considerations• Study design• Sample size• Interim analyses • Choice of outcome variable (endpoints)• Duration of follow up• Post hoc analyses
• Statistical considerations• Study design• Sample size• Interim analyses • Choice of outcome variable (endpoints)• Duration of follow up• Post hoc analyses
Phase 3: Statistical ConsiderationsStudy Design
Factorial Design
Address two questions in one clinical trial
Marginal analysis
Interaction
test for interaction
proof of no interaction: trial sizing
Factorial Design
Address two questions in one clinical trial
Marginal analysis
Interaction
test for interaction
proof of no interaction: trial sizing
Phase 3 Study Design
A Cisplatin
DoxorubicinHDMTX
BIfosfamide
DoxorubicinHDMTX
INDUCTION INDUCTION
Cisplatin, Ifosfamide, Doxorubicin, HDMTXCisplatin, Ifosfamide, Doxorubicin, HDMTX
2020 36362727WeeksWeeks
Cisplatin, Doxorubicin, HDMTXCisplatin, Doxorubicin, HDMTX
MAINTENANCE MAINTENANCE
A
B
Cisplatin, Doxorubicin, HDMTX, Cisplatin, Doxorubicin, HDMTX, MTPMTP
Cisplatin, Ifosfamide,Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Doxorubicin, HDMTX, MTPMTP
A+
B+
DEFINITIVE
SURGERY
DEFINITIVE
SURGERY
Phase 3 Statistical Considerations: Sample size
Sample size:population ratio
Impact on magnitude of error
Regulatory issue: need for confirmatory study
Sample size:population ratio
Impact on magnitude of error
Regulatory issue: need for confirmatory study
Jar holding 1,000 marbles, 700 red, 300 blue
Sample: 50 marbles
Mean: 35 red, 15 blue (70% red)
Standard error of the mean: 6.3%
Jar holding 1,000 marbles, 700 red, 300 blue
Sample: 50 marbles
Mean: 35 red, 15 blue (70% red)
Standard error of the mean: 6.3%
Phase 3 Statistical Considerations: Sample size
Jar holding 1,000 marbles, 700 red, 300 blue
Sample size: 500 marbles
Mean: 350 red, 150 blue (70% red)
Standard error of the mean: 1.5%
Jar holding 1,000 marbles, 700 red, 300 blue
Sample size: 500 marbles
Mean: 350 red, 150 blue (70% red)
Standard error of the mean: 1.5%
Phase 3 Statistical Considerations: Sample size
INT0133 777 patients/48 months
Osteosarcoma incidence 350-400/year
Sample size 48-55% of population
Effect estimate robust, smaller error
INT0133 777 patients/48 months
Osteosarcoma incidence 350-400/year
Sample size 48-55% of population
Effect estimate robust, smaller error
Phase 3 Statistical Considerations: Sample size for MTP in Osteosarcoma
Phase 3 Statistical Considerations:Interim analyses
Timing of interim analyses
Pre-defined by events not elapsed time
Danger of looking too often
Timing of interim analyses
Pre-defined by events not elapsed time
Danger of looking too often
Phase 3 Statistical Considerations:Interim analyses and MTP/Osteosarcoma
Futility
Safety
Three interim analyses
Modified p-value
Futility
Safety
Three interim analyses
Modified p-value
Phase 3 :Statistical ConsiderationsChoice of outcome variable
Progression free survival Event free survival
Median survival 80th percentile survival
Overall survival Quality of life
Progression free survival Event free survival
Median survival 80th percentile survival
Overall survival Quality of life
Pediatric oncology endpoint:NCI position (I)
Strength of Study Design
1. Randomized controlled clinical trial
i. Double-blinded
ii. Non-blinded
Strength of Study Design
1. Randomized controlled clinical trial
i. Double-blinded
ii. Non-blinded
http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment
Pediatric oncology endpoint:NCI position (II)
Strength of Endpoints
A. Total mortality
B. Cause-specific mortality
C. QOL
D. Indirect surrogates
i. EFS
ii. DFS
iii. PFS
iv. Response
Strength of Endpoints
A. Total mortality
B. Cause-specific mortality
C. QOL
D. Indirect surrogates
i. EFS
ii. DFS
iii. PFS
iv. Response
Pediatric oncology endpoint:FDA Position
Patient Access to New Therapeutic Agents for Pediatric Cancer December 2003
Report to Congress
“Surrogate markers could be considered as an early means of identifying efficacy, but the use of surrogates requires validation of these markers and correlation with clinical benefit.”
Patient Access to New Therapeutic Agents for Pediatric Cancer December 2003
Report to Congress
“Surrogate markers could be considered as an early means of identifying efficacy, but the use of surrogates requires validation of these markers and correlation with clinical benefit.”
http://www.fda.gov/cder/Pediatric/BPCA-ReportDec2003.pdf
Phase 3 Statistical Considerations: Outcome variableProgression free survival (PFS)
Wide applicability in sarcoma
Not widely used in “pediatric” sarcomas
Result available relatively quickly
Ascertainment bias
Predetermined evaluation schedule
Central review of imaging
Regulatory considerations
Wide applicability in sarcoma
Not widely used in “pediatric” sarcomas
Result available relatively quickly
Ascertainment bias
Predetermined evaluation schedule
Central review of imaging
Regulatory considerations
Phase 3 Statistical Considerations: Outcome variableEvent free survival (EFS)
Widely employed surrogate for survival
Includes secondary malignancy, toxic deaths
Ascertainment bias
Predetermined evaluation schedule
Central review of imaging
Widely employed surrogate for survival
Includes secondary malignancy, toxic deaths
Ascertainment bias
Predetermined evaluation schedule
Central review of imaging
Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP
Interaction between assigned chemotherapy and MTP was assessed using the proportional hazards regression. A p-value of 0.10 level or less was considered evidence of a significant interaction.
Interaction between assigned chemotherapy and MTP was assessed using the proportional hazards regression. A p-value of 0.10 level or less was considered evidence of a significant interaction.
1 2 120| , c m c mt c m t e
1 2 120| , c m c mt c m t e
1 2 120| , c m c mt c m t e
Event free survival:
Test of the hypothesis of no interaction (p = 0.102)
MTP Hazard ratio [95% CI]
Regimen A 0.99 [0.69, 1.4]
Regimen B 0.65 [0.45, 0.93]
All patients 0.80 [0.62, 1.0]
Event free survival:
Test of the hypothesis of no interaction (p = 0.102)
MTP Hazard ratio [95% CI]
Regimen A 0.99 [0.69, 1.4]
Regimen B 0.65 [0.45, 0.93]
All patients 0.80 [0.62, 1.0]
Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP
Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP
Disease-Free Survival2007 Data (ITT Patients)
Years
Pro
porti
on S
urvi
ving
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MepactNo Mepact
N Events338 107340 133
p=0.0586HR=0.78 (CI: 0.61, 1.01)
Disease-Free Survival2007 Data (ITT Patients)
Years
Pro
porti
on S
urvi
ving
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MepactNo Mepact
N Events338 107340 133
p=0.0586HR=0.78 (CI: 0.61, 1.01)
N Events338 107340 133
p=0.0586HR=0.78 (CI: 0.61, 1.01)
By MTP AssignmentProgression-Free Survival2007 ITT Data
Years
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
IfosNo Ifos
MTPNo MTP
By Chemotherapy Assignment
Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP
Disease-Free Survival2007 Data (ITT Patients)
Months
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events174 62167 58166 71171 49
Disease-Free Survival2007 Data (ITT Patients)
Months
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events174 62167 58166 71171 49
Years
AA + MTPBB + MTP
Phase 3: Statistical Considerations- Outcome variable Survival
Not subject to ascertainment bias
Many years of followup
Lack of QOL data
Not subject to ascertainment bias
Many years of followup
Lack of QOL data
Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma
Overall Survival2007 Data (ITT Patients)
Years
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events174 51167 37166 49171 36
p=0.1935HR=0.75 (CI: 0.49, 1.16)p=0.0806HR=0.68 (CI: 0.44, 1.05)
Overall Survival2007 Data (ITT Patients)
Years
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events174 51167 37166 49171 36
Overall Survival2007 Data (ITT Patients)
Years
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events174 51167 37166 49171 36
p=0.1935HR=0.75 (CI: 0.49, 1.16)p=0.0806HR=0.68 (CI: 0.44, 1.05)
p=0.1935HR=0.75 (CI: 0.49, 1.16)p=0.0806HR=0.68 (CI: 0.44, 1.05)
MTP
MTP
Analysis of Interaction
Overall survival: Test of the hypothesis of no interaction (p = 0.60)
MTP Hazard ratio [95% CI]
Regimen A 0.76 [0.49, 1.2]
Regimen B 0.66 [0.43, 1.0]
All patients 0.71 [0.52, 0.96]
Overall survival: Test of the hypothesis of no interaction (p = 0.60)
MTP Hazard ratio [95% CI]
Regimen A 0.76 [0.49, 1.2]
Regimen B 0.66 [0.43, 1.0]
All patients 0.71 [0.52, 0.96]
Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma
Overall Survival2007 ITT Data
Years
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
IfosNo Ifos
Survival by Chemotherapy Assignment
Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma
Overall Survival2007 Data (ITT Patients)
Years
Pro
port
ion S
urv
ivin
g
0 1 2 3 4 5 6 7 8 9 10 11 12
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MepactNo Mepact
N Deaths338 73340 100
p=0.0313HR=0.72 (CI: 0.53, 0.97)
Overall Survival2007 Data (ITT Patients)
Years
Pro
port
ion S
urv
ivin
g
0 1 2 3 4 5 6 7 8 9 10 11 12
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MepactNo Mepact
N Deaths338 73340 100
p=0.0313HR=0.72 (CI: 0.53, 0.97)
N Deaths338 73340 100
p=0.0313HR=0.72 (CI: 0.53, 0.97)
MTPNo MTP
Survival by MTP Assignment
Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10 12Years
MTP
No MTP
SEER 1993-2002SEER 1987-1992
SEER 1981-1986SEER 1975-1980
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10 12Years
MTP
No MTP
SEER 1993-2002SEER 1987-1992
SEER 1981-1986SEER 1975-1980
Phase 3 Statistical Considerations: Outcome variableQuality of life
Incorporates survival
Adds dimension related to non-lethal toxicity
Increasingly considered optimal endpoint
Incorporates survival
Adds dimension related to non-lethal toxicity
Increasingly considered optimal endpoint
Phase 3: Statistical ConsiderationsDuration of follow-up
Dependent on variable and population
PFS in late stage patients: shorter followup
DFS, EFS in mrd patients – multi year
Survival: need to monitor late effects, need for life time followup
Dependent on variable and population
PFS in late stage patients: shorter followup
DFS, EFS in mrd patients – multi year
Survival: need to monitor late effects, need for life time followup
Cooperative group fiscal decision to close study to followup
Difficulty obtaining followup after official study closure
Older study, no social security numbers
Cooperative group fiscal decision to close study to followup
Difficulty obtaining followup after official study closure
Older study, no social security numbers
Phase 3: Statistical ConsiderationsDuration of follow-up and MTP/Osteosarcoma
Phase 3: Statistical Considerations Duration of follow-up and IGF1R inhibition/sarcoma
Phase II study: PFS, not designed to capture survival
Phase III study: EFS, must be designed to capture survival
Phase II study: PFS, not designed to capture survival
Phase III study: EFS, must be designed to capture survival
Phase 3: Statistical Considerations Post hoc analyses
Analyses of … important subgroups should be a regular part of the evaluation of a clinical
study (when relevant), but should usually be considered exploratory, unless there is a priori
suspicion that one or more of these factors may influence the size of effect”
(CPMP/EWP/908/99).
Analyses of … important subgroups should be a regular part of the evaluation of a clinical
study (when relevant), but should usually be considered exploratory, unless there is a priori
suspicion that one or more of these factors may influence the size of effect”
(CPMP/EWP/908/99).
Phase 3: Statistical Considerations Post hoc analyses and MTP/Osteosarcoma
Hazard Ratio: Mepact vs. No Mepact
Tum. Size 11.0+ cmTum. Size 9.0-10.9 cmTum. Size 7.0-8.9 cmTum. Size 0.2-6.9 cmAlkPhos at or Above ULNAlkPhos Below ULNLDH at or Above ULNLDH Below ULNSESWNWNEPOGCCGOtherBlackHispanicWhiteAge 16+Age 13-15Age 1-12MalesFemales
Overall.2 1 52.5
Subgroups
2007 Overall Survival: Mepact vs. No Mepact Favors MTP
Hazard Ratio: MTP vs No MTP
Subgroup Analysis Caveat
“Clearly significant overall results may therefore provide strong indirect evidence of benefit in subgroups where the results, considered in isolation, are not conventionally significant (or even, perhaps, slightly adverse).”
ISIS-2 (Second International Study of Infarct Survival) Collaboration Group, The Lancet 1988, 2 (8607):349-
360.
“Clearly significant overall results may therefore provide strong indirect evidence of benefit in subgroups where the results, considered in isolation, are not conventionally significant (or even, perhaps, slightly adverse).”
ISIS-2 (Second International Study of Infarct Survival) Collaboration Group, The Lancet 1988, 2 (8607):349-
360.
51
Neoadjuvant Histologic ResponsePatients > 16 Years*Neoadjuvant Histologic ResponsePatients > 16 Years*
Viable Tumor
Grades I/IIUnfavorable
Grades III/IV
Favorable
Not reported** Total
Regimen
MEPACT 57 (59%) 23 (24%) 17 (17%) 97
No MEPACT 40 (47%) 32 (38%) 13 (15%) 85
Total 97 55 30 182
*p=0.0626** Includes patients who progressed before surgery or for whom data not available
52
Neoadjuvant Histologic Response Patients < 16 Years*Neoadjuvant Histologic Response Patients < 16 Years*
Viable Tumor
Grades I/IIUnfavorable
Grades III/IV
Favorable
Not reported** Total
Regimen
MEPACT 109 (45%) 101 (42%) 31 (13%) 241
No MEPACT 116 (45%) 107 (42%) 32 (13%) 255
Total 225 208 63 496
*p=0.9421** Includes patients who progressed before surgery or for whom data not available
Phase 3: Statistical Considerations Post hoc analyses and MTP/Osteosarcoma
Disease-Free Survival2007 Data (ITT Patients Aged < 16)
Months
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events131 48121 35124 50120 32
Disease-Free Survival2007 Data (ITT Patients Aged < 16)
Months
Pro
port
ion
Sur
vivi
ng
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events131 48121 35124 50120 32
DFS <16 yrsOverall Survival
2007 Data (ITT Patients Aged < 16)
Months
Pro
port
ion
Su
rviv
ing
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events131 39121 20124 35120 22
Overall Survival2007 Data (ITT Patients Aged < 16)
Months
Pro
port
ion
Su
rviv
ing
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AA + MepactBB + Mepact
N Events131 39121 20124 35120 22
OS <16 yrs
Years Years
AA + MTPBB + MTP
AA + MTPBB + MTP
Phase 3: Statistical Considerations post hoc analyses - Post relapse survival
Post relapse treatment
alloBMT in hematologic malignancy
Retrieval therapies for solid tumors
Surgery, radiation, chemo
Post relapse treatment
alloBMT in hematologic malignancy
Retrieval therapies for solid tumors
Surgery, radiation, chemo
Phase 3: Statistical Considerations post hoc analyses –
Post relapse survival and MTP in osteosarcoma
Surgical resection of metastatic sites necessary for survival
No impact of chemotherapy on post relapse survival
INT 0133, no difference in surgery for recurrence
Survival is the ultimate endpoint
Surgical resection of metastatic sites necessary for survival
No impact of chemotherapy on post relapse survival
INT 0133, no difference in surgery for recurrence
Survival is the ultimate endpoint
Benefit:Risk Ratio
Introduction of new agents
Robust indication of benefit
Ascertainment of risk in appropriate setting
Favorable benefit:risk ratio argues for early introduction
Introduction of new agents
Robust indication of benefit
Ascertainment of risk in appropriate setting
Favorable benefit:risk ratio argues for early introduction
MTP in osteosarcoma:Benefit:risk ratio
Statistically significant 30% reduction in the risk of death
No grade III or IV toxicity attributed to MTP
Very favorable benefit:risk ratio
Statistically significant 30% reduction in the risk of death
No grade III or IV toxicity attributed to MTP
Very favorable benefit:risk ratio
IGF1R inhibition in sarcoma:Benefit:risk ratio
Phase I, Phase II studies of IGF1R MoAb: favorable toxicity profile
Phase III studies in non-sarcoma indications in combination with chemothearpy: low toxicity
Probable favorable benefit:risk ratio in phase III trials in sarcoma
Phase I, Phase II studies of IGF1R MoAb: favorable toxicity profile
Phase III studies in non-sarcoma indications in combination with chemothearpy: low toxicity
Probable favorable benefit:risk ratio in phase III trials in sarcoma
Regulatory Issues
Requirement for placebo Need for large sample size Requirement for confirmatory studies
Requirement for placebo Need for large sample size Requirement for confirmatory studies
Regulatory issues:Requirement for placebo
Placebos considered unacceptable for minors
MTP associated with fever, chills
What to use for placebo?
IGF1R formulation hard to blind pharmacist
Placebos considered unacceptable for minors
MTP associated with fever, chills
What to use for placebo?
IGF1R formulation hard to blind pharmacist
Regulatory issues:Sample size
Orphan diseases
Track record in pediatric oncology
One phase III randomized study/decade
International collaboration
EURO-Ewing, EURAMOS
Orphan diseases
Track record in pediatric oncology
One phase III randomized study/decade
International collaboration
EURO-Ewing, EURAMOS
MTP in osteosarcoma:Requirement for confirmatory studies
MTP in OS: largest prospective randomized trial ever completed
Sample size = 45-50% population
Robust survival advantage
Favorable benefit:risk ratio
Difficulty mounting successor study
MTP in OS: largest prospective randomized trial ever completed
Sample size = 45-50% population
Robust survival advantage
Favorable benefit:risk ratio
Difficulty mounting successor study
IGF1R inhibition in sarcomas:Requirement for confirmatory studies
European, US regulators
Will require confirmatory studies which demonstrate survival advantage
Plan to acquire survival data from all studies
European, US regulators
Will require confirmatory studies which demonstrate survival advantage
Plan to acquire survival data from all studies
