Development of New Drugs: Lessons from Clinical Trials

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

• 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

• 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

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

0 1 2 3 4 5 6 7 8 9 10 11 12 13

SurvivalDFS

Phase 3: Design Considerations Osteosarcoma

Survival

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

Cisplatin, Doxorubicin, HDMTX, Cisplatin, Doxorubicin, HDMTX, MTPMTP

Cisplatin, Ifosfamide,Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Doxorubicin, HDMTX, MTPMTP

DEFINITIVE

SURGERY

DEFINITIVE

SURGERY

R Introduction of MTP

Phase 3: Design ConsiderationsIGF R Inhibitors

Phase II trials show objective responses

Synergy with chemotherapy

Phase II trials show objective responses

Synergy with chemotherapy

• 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

Cisplatin, Doxorubicin, HDMTX, Cisplatin, Doxorubicin, HDMTX, MTPMTP

Cisplatin, Ifosfamide,Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Doxorubicin, HDMTX, MTPMTP

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%

Sample: 50 marbles

Sample size: 500 marbles

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

Regulatory considerations

Phase 3 Statistical Considerations: Outcome variableEvent free survival (EFS)

Widely employed surrogate for survival

Includes secondary malignancy, toxic deaths

Ascertainment bias

Widely employed surrogate for survival

Includes secondary malignancy, toxic deaths

Ascertainment bias

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.

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)

Regimen A 0.99 [0.69, 1.4]

Regimen B 0.65 [0.45, 0.93]

All patients 0.80 [0.62, 1.0]

Disease-Free Survival2007 Data (ITT Patients)

0 1 2 3 4 5 6 7 8 9 10 11 12 13

MepactNo Mepact

N Events338 107340 133

p=0.0586HR=0.78 (CI: 0.61, 1.01)

0 1 2 3 4 5 6 7 8 9 10 11 12 13

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

0 1 2 3 4 5 6 7 8 9 10 11 12 13

IfosNo Ifos

MTPNo MTP

By Chemotherapy Assignment

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13

AA + MepactBB + Mepact

N Events174 62167 58166 71171 49

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13

N Events174 62167 58166 71171 49

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)

0 1 2 3 4 5 6 7 8 9 10 11 12 13

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)

0 1 2 3 4 5 6 7 8 9 10 11 12 13

N Events174 51167 37166 49171 36

0 1 2 3 4 5 6 7 8 9 10 11 12 13

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)

Analysis of Interaction

Overall survival: Test of the hypothesis of no interaction (p = 0.60)

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)

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 Survival2007 ITT Data

0 1 2 3 4 5 6 7 8 9 10 11 12 13

IfosNo Ifos

Survival by Chemotherapy Assignment

0 1 2 3 4 5 6 7 8 9 10 11 12

MepactNo Mepact

N Deaths338 73340 100

p=0.0313HR=0.72 (CI: 0.53, 0.97)

0 1 2 3 4 5 6 7 8 9 10 11 12

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

0 2 4 6 8 10 12Years

No MTP

SEER 1993-2002SEER 1987-1992

SEER 1981-1986SEER 1975-1980

0 2 4 6 8 10 12Years

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-

“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-

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

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

0 1 2 3 4 5 6 7 8 9 10 11 12 13

N Events131 48121 35124 50120 32

Disease-Free Survival2007 Data (ITT Patients Aged < 16)

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13

N Events131 48121 35124 50120 32

DFS <16 yrsOverall Survival

2007 Data (ITT Patients Aged < 16)

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13

N Events131 39121 20124 35120 22

Overall Survival2007 Data (ITT Patients Aged < 16)

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13

N Events131 39121 20124 35120 22

OS <16 yrs

Years Years

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

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

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