1 Oncologic Drugs Advisory Committee on MTP for Osteosarcoma IDM Pharma, Inc. May 9, 2007 Silver...

1

Oncologic Drugs Oncologic Drugs Advisory CommitteeAdvisory Committee

ononMTP for OsteosarcomaMTP for Osteosarcoma

Oncologic Drugs Oncologic Drugs Advisory CommitteeAdvisory Committee

ononMTP for OsteosarcomaMTP for Osteosarcoma

IDM Pharma, Inc.

May 9, 2007Silver Spring, MD

IDM Pharma, Inc.

May 9, 2007Silver Spring, MD

2001.01

2

Bonnie Mills, PhDBonnie Mills, PhDBonnie Mills, PhDBonnie Mills, PhD

Vice President, Clinical Operations

IDM Pharma

Vice President, Clinical Operations

IDM Pharma

2002.01

3

MTP SponsorsMTP SponsorsMTP SponsorsMTP Sponsors

Ciba-Geigy 1988-1996

Non-clinical and Phase 1/2 studies

NCI 1993-1997

Cooperative Group Phase 3 trial

Jenner Biotherapies 1996-2003

IDM 2003-present

Completed Phase 3 primary final analysis 2004

Submitted NDA 2006

2008.01

4

Phase 3 TrialPhase 3 TrialPhase 3 TrialPhase 3 Trial

Large, well conducted, multi-center study in osteosarcoma (NCI/COG)

Clinically meaningful effect– DFS (primary): p = 0.0245, HR = 0.76, 95% CI (0.58,

0.98)– Survival: p = 0.0183, HR = 0.68, 95% CI (0.49,

0.95)

Subset analyses support internal consistency

Confirmatory study “practically or ethically impossible”

2107.01

5

AgendaAgendaAgendaAgenda

2011.02

Unmet Need Ian Lewis, MB ChB, FRCP, FRCPCHPediatric and Adolescent OncologistSt James University Hospital, Leeds

Product Characteristics

Bonnie Mills, PhDIDM Pharma

Efficacy/Safety Paul Meyers, MD Vice-Chairman, Dept of PediatricsMemorial Sloan-Kettering Cancer Center

Statistical Interpretation

Brent Blumenstein, PhDTrial Architecture Consulting

Benefit/Risk Eugenie Kleinerman, MD Professor and Head, Division of PediatricsMD Anderson Cancer Center

6

Resources and ReferencesResources and ReferencesResources and ReferencesResources and References

Clinical– Curt Scribner, MD– Cheryl Graham, MD

Statistics– Mark Munsell– Neby Bekele, PhD

Nonclinical– Olivier Faure, PhD

Regulatory– Tung Koh

COG Statistician– Mark Krailo, PhD

2117.03

Software Citation: Surveillance Research Program, National Cancer Institute SEER*Stat software (www.seer.cancer.gov/seerstat) version 6.3.5.

Data Citation: Surveillance, Epidemiology, and End Results (SEER) Program(www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Limited-Use, Nov 2004 Sub (1973-2002), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2005, based on the November 2004 submission.

7

Unmet NeedUnmet NeedUnmet NeedUnmet Need

Ian Lewis, MB ChB, FRCP, FRCPCH

Pediatric Oncologist, Leeds, UK

Chief Investigator: European Osteosarcoma Intergroup Randomized Trial 80931

NCI External Program Reviewer

Ian Lewis, MB ChB, FRCP, FRCPCH

Pediatric Oncologist, Leeds, UK

Chief Investigator: European Osteosarcoma Intergroup Randomized Trial 80931

NCI External Program Reviewer2012.02

8

OsteosarcomaOsteosarcomaOsteosarcomaOsteosarcoma

Sites of disease– Metaphyses of long bones particularly

distal femur, proximal tibia and proximal humerus

Clinically evident metastases at diagnosis– Lung alone 20%– Bones/combined 5%

2405.03

9

Single Agent Activity in OsteosarcomaSingle Agent Activity in OsteosarcomaSingle Agent Activity in OsteosarcomaSingle Agent Activity in Osteosarcoma

2407.03

DrugResponses/

Patients Response % Author Year

Doxorubicin 28/109 26 Cortes 1972

Cisplatin 8/24 33 Nitschke 1978Ochs 1978

HD MTX (wkly) 9/11 82 Jaffe 1977

HD MTX (3wkly) 11/26 42 Jaffe 1973Pratt 1980

Ifosfamide 6/18 33 Marti 1985

10

0

20

40

60

80

100

1960-4 1965-9 1970-4 1975-9 1980-4 1985-9 1990-4 1995-9 2000-4

Pe

rce

nt

UK Osteosarcoma Survival 1960-2000UK Osteosarcoma Survival 1960-2000UK Osteosarcoma Survival 1960-2000UK Osteosarcoma Survival 1960-2000

Historical:

Surgery alone

Historical:

Surgery alone

Introduction of chemotherapyIntroduction of chemotherapy

Attempted refinement of chemotherapyAttempted refinement of chemotherapy

2406.02

11

EOI 80931 Randomized Trial Doxorubicin/ EOI 80931 Randomized Trial Doxorubicin/ Cisplatin: Standard vs Intensified Cisplatin: Standard vs Intensified EOI 80931 Randomized Trial Doxorubicin/ EOI 80931 Randomized Trial Doxorubicin/ Cisplatin: Standard vs Intensified Cisplatin: Standard vs Intensified

2019.02 Lewis et al, J Natl Cancer Inst. 2007. 99:112-28

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Log rank p-value = 0.52Hazard Ratio = 1.10 (95% CI 0.83–1.46)

Years0 1 2 3 4 5 6 7

StandardIntensified 91 254

98 250Events Total 5 year

55%

58%

12

Osteosarcoma Survival by Time EpochOsteosarcoma Survival by Time Epoch(SEER Ages 0 – 29)(SEER Ages 0 – 29)Osteosarcoma Survival by Time EpochOsteosarcoma Survival by Time Epoch(SEER Ages 0 – 29)(SEER Ages 0 – 29)

2094.04

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

1993-20021987-1992

1981-19861975-1980

13

Product CharacteristicsProduct CharacteristicsProduct CharacteristicsProduct Characteristics

Bonnie Mills, PhDBonnie Mills, PhD

2009.01

14

Spacer

Muramyl Tripeptide-Phosphatidyl Muramyl Tripeptide-Phosphatidyl Ethanolamine (MTP-PE)Ethanolamine (MTP-PE)Muramyl Tripeptide-Phosphatidyl Muramyl Tripeptide-Phosphatidyl Ethanolamine (MTP-PE)Ethanolamine (MTP-PE)

MTP

MDP PE

2005.01

15

Liposomal MTP-PELiposomal MTP-PELiposomal MTP-PELiposomal MTP-PE

2003.03

MTP-PE

MTP-PE

16

Cytosol

Macrophage

Administration of MTPAdministration of MTPAdministration of MTPAdministration of MTP

NOD2MTP MTPMTPMTP

1 hour 5 hours

IL- 1

IL- 8

IL- 6

TNFa

Adapted from Strober W., Nature Rev Immunol, 6:9-20, 2006

2437.01

17

MTP Induces Infiltration of Inflammatory MTP Induces Infiltration of Inflammatory Macrophages into Lung MetastasesMacrophages into Lung MetastasesMTP Induces Infiltration of Inflammatory MTP Induces Infiltration of Inflammatory Macrophages into Lung MetastasesMacrophages into Lung Metastases

Kleinerman Kleinerman et al.et al., , Cancer Immunol. ImmunotherCancer Immunol. Immunother., 1992., 1992

Without MTP With MTP

2006.01

18

EfficacyEfficacyEfficacyEfficacy

Paul Meyers, MD

Vice-Chairman, Dept of PediatricsMemorial Sloan-Kettering Cancer Center

Paul Meyers, MD

Vice-Chairman, Dept of PediatricsMemorial Sloan-Kettering Cancer Center

2023.01

19

Osteosarcoma Survival:Osteosarcoma Survival:SEER DataSEER DataOsteosarcoma Survival:Osteosarcoma Survival:SEER DataSEER Data

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

1993-2002

2503.01

20

Phase 2 Results in Relapsed Osteosarcoma Phase 2 Results in Relapsed Osteosarcoma with Lung Metastaseswith Lung MetastasesPhase 2 Results in Relapsed Osteosarcoma Phase 2 Results in Relapsed Osteosarcoma with Lung Metastaseswith Lung Metastases

2025.04 Kleinerman ES et al, Am.J. Clin. Onc. 18:93, 1995

Dis

ease

-Fre

e S

urvi

val

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

Years

FailTotal

Historical control2021

MTP Cohort 2 (24wk)1116

MTP Cohort 1 (12wk)1212

00 101088664422 1212

21

Landmark Phase 3 TrialLandmark Phase 3 TrialLandmark Phase 3 TrialLandmark Phase 3 Trial

NCI-sponsored, Cooperative Group study– Designed and conducted independently of corporate

sponsor

Largest study completed in osteosarcoma– 178 sites – 1/3 of eligible incident cases in US

Newly diagnosed (within 30 days; age <31)– 678 non-metastatic resectable disease– 115 with more advanced disease

2027.01

22

Phase 3 Study DesignPhase 3 Study DesignPhase 3 Study DesignPhase 3 Study Design

A Cisplatin

DoxorubicinHDMTX

2028.03

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

23

Phase 3 Study EndpointsPhase 3 Study EndpointsPhase 3 Study EndpointsPhase 3 Study Endpoints

DFS – Putative surrogate for OS– Prospectively defined primary endpoint– “To determine whether MTP can improve DFS…”– “To compare the results of a prospective, randomized

trial of two chemotherapeutic regimens…” (A vs. B)

Survival– “To improve the survival of patients with osteogenic

sarcoma”

2034.02

24

Data SourcesData SourcesData SourcesData Sources

IDM

Patient RecordsPatient

Records


Records


Records

Clinical Sites

COG

CRFsCRFs11

2403.03

22DatabaseDatabase

2003200333 33

25

Baseline Demographics and Disease Baseline Demographics and Disease CharacteristicsCharacteristicsBaseline Demographics and Disease Baseline Demographics and Disease CharacteristicsCharacteristics

2120.03

A-(n=174)

A+(n=167)

B- (n=166)

B+(n=171)

SexMale 49% 57% 52% 61%Female 51% 43% 48% 39%

Mean age (range)

13.8 (4.0-30.1)

14.0 (4.9-29.2)

13.5 (4.2-30.6)

13.8 (1.4-30.4)

Race/EthnicityWhite 67% 65% 72% 61%Hispanic 11% 16% 10% 13%Black 15% 12% 15% 16%Other 7% 7% 3% 10%

SiteHumerus 10% 13% 10% 12%Femur 52% 54% 58% 53%Tibia 23% 27% 23% 27%Other 15% 6% 9% 8%

26

Primary Analysis: DFSPrimary Analysis: DFSPrimary Analysis: DFSPrimary Analysis: DFS

ArmRelapse

Deaths (N) p-value

HazardRatio

(95% CI)

6-YearDFS

Probability

No MTP 126 (340)

0.0245¹ 0.76(0.58, 0.98)

57%

66%MTP 102 (338)

¹p-value from log-rank test stratified by chemotherapy use and randomization strata2003 ITT2134.01

27

Primary Analysis: DFS (Kaplan-Meier)Primary Analysis: DFS (Kaplan-Meier)Primary Analysis: DFS (Kaplan-Meier)Primary Analysis: DFS (Kaplan-Meier)

2041.03

Disease-Free Survival2003 ITT

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

MTPno MTP

N338340

Events102126

No MTP

MTP

29

Primary Analysis: SurvivalPrimary Analysis: SurvivalPrimary Analysis: SurvivalPrimary Analysis: Survival

Arm Deaths (N) p-value

HazardRatio

(95% CI)

6-YearSurvival

Probability

No MTP 85 (340)

0.0183¹ 0.68(0.49, 0.95)

66%

77%MTP 63 (338)


30

Primary Analysis: Survival (Kaplan-Meier)Primary Analysis: Survival (Kaplan-Meier)Primary Analysis: Survival (Kaplan-Meier)Primary Analysis: Survival (Kaplan-Meier)

2038.04

MTP

No MTP

2003 ITTOverall Survival

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

MTPno MTP

N338340

Events6385

32

Data SourcesData SourcesData SourcesData Sources

IDM


Records


Records


Records

Clinical Sites

COG

CRFCRF11 22

DatabaseDatabase

20062006 33

2455.01

33

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

2229.05

Follow Up 2003 and 2006Follow Up 2003 and 2006Follow Up 2003 and 2006Follow Up 2003 and 2006

2003 ITT

MTP

no MTP

2006 ITT

MTP

no MTP

Time to Last Contact Time to Last Contact

34

Confirmatory Analysis 2006: SurvivalConfirmatory Analysis 2006: SurvivalConfirmatory Analysis 2006: SurvivalConfirmatory Analysis 2006: Survival

Arm Deaths (N) p-value

HazardRatio

(95% CI)

6-YearSurvival

Probability

No MTP 100 (340)

0.0352¹ 0.72(0.53, 0.97)

70%

78%MTP 73 (338)


35

Confirmatory 2006 Analysis: Survival Confirmatory 2006 Analysis: Survival (Kaplan-Meier)(Kaplan-Meier)Confirmatory 2006 Analysis: Survival Confirmatory 2006 Analysis: Survival (Kaplan-Meier)(Kaplan-Meier)

2223.03

2006 DataOverall Survival

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

MTPno MTP

N338340

Events73

100

MTP

No MTP

36

SafetySafetySafetySafety

2457.01

37

Grade 3 or 4 Adverse Events Reported by Grade 3 or 4 Adverse Events Reported by ≥3% of Patients: Phase 3 ITT≥3% of Patients: Phase 3 ITT Grade 3 or 4 Adverse Events Reported by Grade 3 or 4 Adverse Events Reported by ≥3% of Patients: Phase 3 ITT≥3% of Patients: Phase 3 ITT

Adverse Event

No MTP

N=340

N (%)

MTP

N=338

N (%) P-value

Stomatitis 155 (46) 155 (46)

Infection 81 (24) 73 (22)

Vomiting 59 (17) 59 (17)

Hearing - objective 24 (7) 39 (12) 0.048

Hearing - subjective 2 (1) 12 (4) 0.007

Ileus 9 (3) 10 (3)

Diarrhea 11 (3) 14 (4)

Skin 22 (6) 15 (4)

Abdominal Pain 7 (2) 11 (3)

CNS/Cerebellar 14 (4) 13 (4)

Mood 9 (3) 9 (3)

2428.01

38

Patient Discontinuation (Maintenance)Patient Discontinuation (Maintenance)Patient Discontinuation (Maintenance)Patient Discontinuation (Maintenance)

2122.02

A-

174

A+

167

B-

166

B+

171

Treated following surgery 153 145 148 158

Withdrawn

Progressive Disease 9 8 7 9

Removed for Toxicity 1 1 4 2

Withdrawal by Parent or Patient 8 20 6 26

Withdrawal by Physician 0 1 4 6

Major Protocol Deviation 2 5 5 4

Death 1 1 0 1

Lost to Follow-Up 0 1 0 1

Other 0 0 1 2

Deemed Ineligible 2 0 1 1

39

Osteosarcoma: Overall SurvivalOsteosarcoma: Overall Survival(SEER Ages 0 - 29)(SEER Ages 0 - 29)Osteosarcoma: Overall SurvivalOsteosarcoma: Overall Survival(SEER Ages 0 - 29)(SEER Ages 0 - 29)

2094.04

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

1993-20021987-1992

1981-1986

1975-1980

40

Osteosarcoma: Overall SurvivalOsteosarcoma: Overall SurvivalSEER and COG 2006 Data (All Patients)SEER and COG 2006 Data (All Patients)Osteosarcoma: Overall SurvivalOsteosarcoma: Overall SurvivalSEER and COG 2006 Data (All Patients)SEER and COG 2006 Data (All Patients)

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

2504.01

Statistical ConsiderationsStatistical ConsiderationsStatistical ConsiderationsStatistical Considerations

Brent Blumenstein, PhDBrent Blumenstein, PhD

2458.02

42

Primary AnalysesPrimary AnalysesPrimary AnalysesPrimary Analyses

MTP factor: DFS, 2003 ITT– MTP versus no MTP (228 events):

p = 0.0245 (against 0.04) Hazard ratio = 0.76, 95% CI (0.58, 0.98) Meets statistical criterion

Chemotherapy factor: DFS, 2003 ITT– A versus B (228 events):

p = 0.8331 Hazard ratio = 0.97, 95% CI (0.76, 1.26) Does not meet statistical criterion

Primary analysis issues:– Timing of primary final analysis– DFS Interaction– Consequences of randomization timing

2443.02

43

Timing of the DFS Primary AnalysesTiming of the DFS Primary AnalysesTiming of the DFS Primary AnalysesTiming of the DFS Primary Analyses

Goal– Conform to original statistical goals– Assess impact of deferred final primary analysis

Method– Used simulation– Interim analyses included in simulation

Finding: Refer primary analysis p-value, 0.0245, to 0.034 instead of 0.04

Conclusion: Deferred final analysis OK

2518.01

44

DFS InteractionDFS InteractionDFS InteractionDFS Interaction

Interaction test significance level = 0.1

MTP x Chemo Interaction test: p = 0.06

MTP HRs – A+ vs A-: HR = 0.96– B+ vs B-: HR = 0.63

Qualitative MTP interaction test: no evidence(Gail & Simon, Biometrics 41:361-72, 1985)

Quantitative interaction– Does not invalidate marginal MTP inference– Overall MTP HR = 0.74 (average effect)

2446.02

45

2003 ITT

Kaplan-Meier DFS (A-, A+, B-, B+)Kaplan-Meier DFS (A-, A+, B-, B+)Kaplan-Meier DFS (A-, A+, B-, B+)Kaplan-Meier DFS (A-, A+, B-, B+)

2459.02

N Events

——B+ 171 47

——A+ 167 55

——B- 166 67

——A- 174 59

46

Kaplan-Meier Survival (A-, A+, B-, B+)Kaplan-Meier Survival (A-, A+, B-, B+)Kaplan-Meier Survival (A-, A+, B-, B+)Kaplan-Meier Survival (A-, A+, B-, B+)

2106.03

2003 ITT

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

N Events

—— B+ 171 30

—— A+ 167 33

—— B- 166 42

—— A- 174 43

Interaction p = 0.5269A+ vs A-: HR = 0.76B+ vs B-: HR = 0.61

47

DFS InteractionDFS InteractionDFS InteractionDFS Interaction

Four-arm model (p = 0.0525, 3 df)– Six possible 2-way comparisons

Only significant comparison is B versus B+MTP All others differences consistent with chance

Interaction not present in survival analyses

2447.01

48

Kaplan-Meier Survival (A-, A+, B-, B+)Kaplan-Meier Survival (A-, A+, B-, B+)Kaplan-Meier Survival (A-, A+, B-, B+)Kaplan-Meier Survival (A-, A+, B-, B+)2006 Data

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

N Events

—— B+ 171 36

—— A+ 167 37

—— B- 166 49

—— A- 174 51

2546.01

492448.04

Timing of RandomizationTiming of RandomizationTiming of RandomizationTiming of Randomization2006 ITT

Maintenance N Deaths

—— MTP 303 60

—— No MTP 301 81No Maintenance—— MTP 22 7

—— No MTP 21 8Early Prog/Tox—— MTP 13 6

—— No MTP 18 11

2006 ITT

2006 Survival

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Year

50

Survival Is the Gold Standard Endpoint in Survival Is the Gold Standard Endpoint in OncologyOncologySurvival Is the Gold Standard Endpoint in Survival Is the Gold Standard Endpoint in OncologyOncology

Survival not positive Survival positive

DFS not positive No benefit Likely benefit

DFS positive Doubtful benefit Clear benefit

2450.01

51

Statistical SummaryStatistical SummaryStatistical SummaryStatistical Summary

2003 ITT (primary result)– DFS

p = 0.0245 HR = 0.76, 95% CI (0.58, 0.98) Robust against issues: alpha, interaction, drop-outs

– Survival p = 0.0183 HR = 0.68 95% CI (0.49, 0.95)

2006 ITT (confirmatory result)– Survival

p = 0.035 HR = 0.72 95% CI (0.53, 0.97)

2501.01

Benefits and RisksBenefits and RisksBenefits and RisksBenefits and Risks

Eugenie Kleinerman, MDProfessor and Head, Division of Pediatrics

MD Anderson Cancer Center

Eugenie Kleinerman, MDProfessor and Head, Division of Pediatrics

MD Anderson Cancer Center

2074.01

53

SafetySafetySafetySafety

Side effects reflect activity of MTP

Flu-like symptoms; treated with acetaminophen

No increase in chemo toxicity

Optimal biologic dose < Maximum tolerated dose

Compliance rather than safety concerns

2078.01

54

Consistency of Efficacy Results: ITTConsistency of Efficacy Results: ITTConsistency of Efficacy Results: ITTConsistency of Efficacy Results: ITT

2003 IT TDisease-F ree Survival

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Y ears

M TPno M TP

N338340

Events102126

2003 IT TOverall Survival

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 10 11 12Y earsA t R isk:

338 311 284 252 201 137 69 28 7 0340 298 272 231 172 114 49 19 5 1 0

M TPno M TP

Events6385

N Events

MTP 338 63

No MTP 340 85

N Events

MTP 338 102

No MTP 340 126

2006 D a taDisease-F ree Survival

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Y ears

M TPno M TP

N338340

Events107133

2006 D a taOverall Survival

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 10 11 12Y earsA t R isk:

338 320 297 276 243 206 173 147 123 82 42 16 2340 318 294 266 231 205 166 142 111 80 41 14 3

M TPno M TP

Events73

100 85340No MTP

63338MTP

EventsN

133340No MTP

107338MTP

EventsN

2519.01

55

Consistency of Efficacy Results: MetastaticConsistency of Efficacy Results: MetastaticConsistency of Efficacy Results: MetastaticConsistency of Efficacy Results: Metastatic

2006 Non-ITT DataOverall Survival

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 10 11 12YearsAt R is k:

57 47 32 26 25 24 22 19 13 5 2 1 058 47 33 26 21 15 14 13 11 8 4 1 0

MTPno MTP

Events2232

2006 Non-ITT DataDisease-Free Survival

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 9 10 11 12YearsAt R is k:

57 40 28 22 21 20 19 16 12 4 2 1 058 36 23 17 13 10 9 8 7 6 4 1 0

MTPno MTP

Events2739

N Events

MTP 57 22

No MTP 58 32

N Events

MTP 57 27

No MTP 58 39

2520.01

56

Survival: 2006 ITTSurvival: 2006 ITTSurvival: 2006 ITTSurvival: 2006 ITT

MTP

No MTP

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Years

2521.01

57

SummarySummarySummarySummary

Over 20 years of data with MTP in young people

Phase 3 trial designed to determine efficacy

Phase 3 study is largest US trial in osteosarcoma

No new agents for osteosarcoma since MTX approved

Survival data translate into 50 more cures per year

2522.01

59

Overall Survival (patients with active disease at Overall Survival (patients with active disease at last contact considered dead at last contact): last contact considered dead at last contact): 2006 ITT2006 ITT


Variable# Pts

(events)6-Year OS Probability P-value

Hazard Ratio

95% CIfor HR

No MTP 340 (109) 0.680

0.0401 0.74 (0.55, 0.98)

MTP 338 (82) 0.756

¹P-value from log-rank test stratified by ifosfamide use and randomization strata.

2533.01

60



Variable# Pts

(events)6-Year OS Probability P-value

Hazard Ratio

95% CIfor HR

No MTP 340 (96) 0.609

0.0461 0.75 (0.55, 1.01)

MTP 338 (78) 0.724

¹P-value from log-rank test stratified by ifosfamide use and randomization strata.

2532.01

61

FDA Modified 2003 COG DatasetFDA Modified 2003 COG DatasetFDA Modified 2003 COG DatasetFDA Modified 2003 COG Dataset

Modifications based on FDA review of 2003 CRFs– 7/14 ineligible patients excluded from ITT– New censor dates (2003 data)

Most (>30) ‘synchrony’ modifications 4 last follow up not in CRF – from another COG database 3 lost to follow up, last report excluded

– Event changes/additions (2003 data) death not on correct CRF 1 relapse not reported but surgery for mets reported 1 anecdotal relapse (mentioned in a letter but no date) 1 surgery for benign lesions counted as relapse 2 failures to respond to induction counted as relapse rejected one estimated relapse date by COG

Inclusion of data from one site’s response to IDM’s 2005 audit– 28 patients including 5 new events

2502.01

62

Ototoxicity: Cisplatin and MTP Ototoxicity: Cisplatin and MTP Ototoxicity: Cisplatin and MTP Ototoxicity: Cisplatin and MTP

2294.02

RegimenInductionCisplatin(mg/m2)

MaintenanceCisplatin(mg/m2)

Regimen A 2 x 120 2 x 120

Regimen A + MTP 2 x 120 2 x 120 + MTP

Regimen B 0 4 x 120

Regimen B + MTP 0 4 x 120 + MTP

63

Follow-up to 5 years: 2006 ITTFollow-up to 5 years: 2006 ITTFollow-up to 5 years: 2006 ITTFollow-up to 5 years: 2006 ITTIneligible Eligible

# Complete this interval

or later

% Complete this interval

or later Years Censor LTFU Died Censor LTFU Died Total

MTP0.00-0.99 2 0 0 5 4 7 18 338 100.0%

1.00-1.99 0 0 1 3 4 15 23 327 96.7%

2.0-2.9 0 0 0 6 1 14 21 320 94.7%

3.0-3.9 0 0 1 13 4 14 32 313 92.6%

4.0-4.9 1 0 0 25 3 9 38 296 87.6%

5.0-5.9 0 0 0 25 2 6 33 267 79.0%No MTP

0.00-0.99 3 0 0 3 2 14 22 340 100.0%

1.00-1.99 0 0 2 1 2 19 24 332 97.6%

2.0-2.9 0 0 0 5 1 22 28 329 96.8%

3.0-3.9 0 0 0 16 3 16 35 323 95.0%

4.0-4.9 0 1 0 16 2 8 27 304 89.4%

5.0-5.9 0 0 0 26 0 12 38 285 83.8%2471.01

64

2006 DataOverall Survival

0%

20%

40%

60%

80%

100%

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

174 160 147 135 118 106 84 73 53 39 22 9 2167 157 142 132 114 101 85 78 64 40 19 8 1166 158 147 131 113 98 82 69 58 41 19 5 1171 163 155 144 129 105 88 69 59 42 23 8 1

AA+MTPBB+MTP

Events51374936

2006 Data

OS by Individual Study Arm – 2006 UpdateOS by Individual Study Arm – 2006 UpdateOS by Individual Study Arm – 2006 UpdateOS by Individual Study Arm – 2006 Update

Reg HR

A- 1.00

A+ 0.74

B- 0.97

B+ 0.68

2376.01

65

Treatment: Neoadjuvant Chemotherapy Treatment: Neoadjuvant Chemotherapy ResponseResponseTreatment: Neoadjuvant Chemotherapy Treatment: Neoadjuvant Chemotherapy ResponseResponse

Viable Tumor > 50% 5%-50% < 5% unknown Total

Regimen

A 28 (16%) 50 (29%) 71 (41%) 25 (14%) 174

A + MTP 34 (20%) 59 (35%) 52 (31%) 22 (13%) 167

B 16 (10%) 62 (37%) 68 (41%) 20 (12%) 166

B + MTP 21 (12%) 52 (30%) 72 (42%) 26 (15%) 171

Total 99 223 263 93 678

2184.01

1 Oncologic Drugs Advisory Committee on MTP for Osteosarcoma IDM Pharma, Inc. May 9, 2007 Silver...

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Transcript of 1 Oncologic Drugs Advisory Committee on MTP for Osteosarcoma IDM Pharma, Inc. May 9, 2007 Silver...