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 Paul A. Meyers, MD Vice-Chair, Pediatrics Memorial Sloan-Kettering Professor of Pediatrics Weill Cornell Medical College

Combining biological agents with chemotherapy Phase 1 l Safety profile l Pharmacology l Active dose/MTD Phase 2 Preliminary efficacy Design considerations Phase 3 l Design considerations l Choice of outcome variable l Statistical considerations l Duration of followup Benefit-risk ratio & regulatory considerations Phase 1 l Safety profile l Pharmacology l Active dose/MTD Phase 2 Preliminary efficacy Design considerations Phase 3 l Design considerations l Choice of outcome variable l Statistical considerations l 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/m 2 MTD (<grade 3 events) 4-6mg/m 2 Phase 1 studies in patients with late stage cancers Anecdotal responses Optimal biologic activity.5-2mg/m 2 MTD (<grade 3 events) 4-6mg/m 2

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 ) Obtain evidence of efficacy in target indication Extend safety information Obtain information needed to plan randomized efficacy studies Larger group of patients (usually ) 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 l 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 l 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 l Phase I/II trials suggest use in mrd l Introduce after surgical resection of clinically detectable disease Timing of introduction l Phase I/II trials suggest use in mrd l 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

Phase 3: Design Considerations Osteosarcoma Survival DFS

Phase 3 Study Design A Cisplatin Doxorubicin HDMTX B Ifosfamide Doxorubicin HDMTX INDUCTION Cisplatin, Ifosfamide, Doxorubicin, HDMTX Weeks Cisplatin, Doxorubicin, HDMTX MAINTENANCE A B Cisplatin, Doxorubicin, HDMTX, MTP Cisplatin, Ifosfamide, Doxorubicin, HDMTX, MTP A+ B+ DEFINITIVESURGERYDEFINITIVESURGERY DEFINITIVESURGERYDEFINITIVESURGERY RIntroduction of MTP

Phase 3: Design Considerations IGF R Inhibitors Timing of introduction l Phase II trials show objective responses l Synergy with chemotherapy Timing of introduction l Phase II trials show objective responses l 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 Considerations Study 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 Doxorubicin HDMTX B Ifosfamide Doxorubicin HDMTX INDUCTION Cisplatin, Ifosfamide, Doxorubicin, HDMTX Weeks Cisplatin, Doxorubicin, HDMTX MAINTENANCE A B Cisplatin, Doxorubicin, HDMTX, MTP Cisplatin, Ifosfamide, Doxorubicin, HDMTX, MTP A+ B+ DEFINITIVESURGERYDEFINITIVESURGERY DEFINITIVESURGERYDEFINITIVESURGERY

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

INT patients/48 months Osteosarcoma incidence /year Sample size 48-55% of population Effect estimate robust, smaller error INT patients/48 months Osteosarcoma incidence /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 Considerations Choice of outcome variable Progression free survival Event free survival l Median survival l 80 th percentile survival Overall survival Quality of life Progression free survival Event free survival l Median survival l 80 th 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

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.”

Phase 3 Statistical Considerations: Outcome variable Progression 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 variable Event 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.

Event free survival: Test of the hypothesis of no interaction (p = 0.102) MTP Hazard ratio [95% CI] Regimen A0.99 [0.69, 1.4] Regimen B0.65 [0.45, 0.93] All patients0.80 [0.62, 1.0] Event free survival: Test of the hypothesis of no interaction (p = 0.102) MTP Hazard ratio [95% CI] Regimen A0.99 [0.69, 1.4] Regimen B0.65 [0.45, 0.93] All patients0.80 [0.62, 1.0] Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP

By MTP Assignment MTP No MTP By Chemotherapy Assignment

Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP Years A A + MTP B B + 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 MTP

Analysis of Interaction Overall survival: Test of the hypothesis of no interaction (p = 0.60) MTP Hazard ratio [95% CI] Regimen A0.76 [0.49, 1.2] Regimen B0.66 [0.43, 1.0] All patients0.71 [0.52, 0.96] Overall survival: Test of the hypothesis of no interaction (p = 0.60) MTP Hazard ratio [95% CI] Regimen A0.76 [0.49, 1.2] Regimen B0.66 [0.43, 1.0] All patients0.71 [0.52, 0.96]

Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma Survival by Chemotherapy Assignment

Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma MTP No MTP Survival by MTP Assignment

Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma

Phase 3 Statistical Considerations: Outcome variable Quality 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 Considerations Duration 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 Considerations Duration 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).

Phase 3: Statistical Considerations Post hoc analyses and MTP/Osteosarcoma 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): “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):

51 Neoadjuvant Histologic Response Patients > 16 Years* Viable Tumor Grades I/II Unfavorable Grades III/IV Favorable Not reported** Total Regimen MEPACT57 (59%)23 (24%)17 (17%)97 No MEPACT40 (47%)32 (38%)13 (15%)85 Total *p= ** Includes patients who progressed before surgery or for whom data not available

52 Neoadjuvant Histologic Response Patients < 16 Years* Viable Tumor Grades I/II Unfavorable Grades III/IV Favorable Not reported** Total Regimen MEPACT109 (45%)101 (42%)31 (13%)241 No MEPACT116 (45%)107 (42%)32 (13%)255 Total *p= ** Includes patients who progressed before surgery or for whom data not available

Phase 3: Statistical Considerations Post hoc analyses and MTP/Osteosarcoma DFS <16 yrs OS <16 yrs Years A A + MTP B B + MTP A A + MTP B B + 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