Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004 Pediatric Acute Leukemia December 1, 2004

Clofarabine ODAC PresentationClofarabine ODAC PresentationClofarabine ODAC PresentationClofarabine ODAC Presentation

Pediatric Acute Leukemia

December 1, 2004


December 1, 2004


Steve Weitman, MD, PhDChief Medical OfficerILEX Oncology, Inc.

Steve Weitman, MD, PhDChief Medical OfficerILEX Oncology, Inc.

3

Clofarabine ODAC ConsultantsClofarabine ODAC Consultants

Sima Jeha, MDSt. Jude Children’s Research Hospital

Ka Wah Chan, MDM.D. Anderson Cancer Center

Laurel Steinherz, MDMemorial Sloan-Kettering Cancer Center

Robert Arceci, MD, PhDSidney Kimmel CCC at Johns Hopkins

Sima Jeha, MDSt. Jude Children’s Research Hospital

Ka Wah Chan, MDM.D. Anderson Cancer Center

Laurel Steinherz, MDMemorial Sloan-Kettering Cancer Center

Robert Arceci, MD, PhDSidney Kimmel CCC at Johns Hopkins

Peter Steinherz, MDMemorial Sloan-Kettering Cancer Center

Stephen Sallan, MDDana-Farber Cancer Institute

Varsha Gandhi, PhDM.D. Anderson Cancer Center

Eric Sandler, MDNemours Children’s Clinic

Peter Adamson, MDChildren’s Hospital of Philadelphia

Peter Steinherz, MDMemorial Sloan-Kettering Cancer Center

Stephen Sallan, MDDana-Farber Cancer Institute

Varsha Gandhi, PhDM.D. Anderson Cancer Center

Eric Sandler, MDNemours Children’s Clinic

Peter Adamson, MDChildren’s Hospital of Philadelphia

4

AgendaAgendaIntroduction Steve Weitman, MD, PhD

Pediatric Leukemia: Robert Arceci, MD, PhDNeed for New Treatment Options Sidney Kimmel CCC at

Johns Hopkins

Clofarabine Pivotal Studies Steve Weitman, MD, PhD

Clinician’s Perspective Stephen Sallan, MDDana-Farber Cancer Institute

Clofarabine Development Plan Steve Weitman, MD, PhD

Introduction Steve Weitman, MD, PhD

Pediatric Leukemia: Robert Arceci, MD, PhDNeed for New Treatment Options Sidney Kimmel CCC at

Johns Hopkins

Clofarabine Pivotal Studies Steve Weitman, MD, PhD

Clinician’s Perspective Stephen Sallan, MDDana-Farber Cancer Institute

Clofarabine Development Plan Steve Weitman, MD, PhD

The ChallengeThe Challenge

Robert Arceci, MD, PhDRobert Arceci, MD, PhD

Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsDepartments of Oncology and Pediatrics

Pediatric Leukemia:Pediatric Leukemia:Need for New Treatment OptionsNeed for New Treatment OptionsPediatric Leukemia:Pediatric Leukemia:Need for New Treatment OptionsNeed for New Treatment Options

6

Treatment of Patients with Pediatric LeukemiasTreatment of Patients with Pediatric Leukemias

Treatments for newly diagnosed patients with ALL & AML use aggressive multi-drug regimens

Overall survival for pediatric ALL and AML

has improved, but is approaching a plateau

20% ALL and 50% AML have disease recurrence

Treatments for newly diagnosed patients with ALL & AML use aggressive multi-drug regimens

Overall survival for pediatric ALL and AML

has improved, but is approaching a plateau

20% ALL and 50% AML have disease recurrence

7

Common Pediatric CancersCommon Pediatric Cancers

De Novo ALL & AML (3,000 cases)

CNS (2,200 cases)

Relapsed ALL & AML (900 cases)

Hodgkins (875 cases)

Neuroblastoma (650 cases)

Wilms' (500 cases)

Osteosarcoma (400 cases)

Rhabdomyosarcoma (350 cases)

Ewing's (200 cases)

Hepatic (150 cases)

De Novo ALL & AML (3,000 cases)

CNS (2,200 cases)

Relapsed ALL & AML (900 cases)

Hodgkins (875 cases)

Neuroblastoma (650 cases)

Wilms' (500 cases)

Osteosarcoma (400 cases)

Rhabdomyosarcoma (350 cases)

Ewing's (200 cases)

Hepatic (150 cases)

De NovoALL & AML

CNS

Source: SEER Pediatric MonographAssumes: 75% ALL cases cured and 50% AML cases cured

Relapsed/ RefractoryALL & AML

8

Challenges in Pediatric Relapsed & Refractory LeukemiasChallenges in Pediatric Relapsed & Refractory Leukemias

Heterogeneous population

Multi-drug resistance is common in leukemia cells, particularly at relapse

Dose intensification with combination therapies has resulted in significant co-morbidities and organ dysfunction

Transplant is the best curative option but requires disease control and time to identify donor

Heterogeneous population

Multi-drug resistance is common in leukemia cells, particularly at relapse

Dose intensification with combination therapies has resulted in significant co-morbidities and organ dysfunction

Transplant is the best curative option but requires disease control and time to identify donor

9

0%

50%

100%

0 1 2 3 4 5 6Years Followed

Pro

bab

ilit

y o

f S

urv

ival

Survival in Relapsed/ Refractory Pediatric Leukemia Survival in Relapsed/ Refractory Pediatric Leukemia

Weitman, et. al. J Pediatr Hematol Oncol. 1997;17:197-207

Acute Lymphoid Leukemia

Acute Myeloid Leukemia

10

New Agents Needed for Remission Induction in Relapsed/ Refractory PatientsNew Agents Needed for Remission Induction in Relapsed/ Refractory Patients

Few agents have been approved for pediatric leukemiaMost commonly used agents approved many years ago

Methotrexate (1953) 6-Mercaptopurine (1953)Vincristine (1963)Ara-C (1969)Doxorubicin (1974)

Development of new pediatric oncology agents has lagged behind adult oncology drug development

Few agents have been approved for pediatric leukemiaMost commonly used agents approved many years ago

Methotrexate (1953) 6-Mercaptopurine (1953)Vincristine (1963)Ara-C (1969)Doxorubicin (1974)

Development of new pediatric oncology agents has lagged behind adult oncology drug development

11

ConclusionsConclusions

Relapsed leukemia is the third most common childhood cancer

Successful treatment of relapsed and refractory pediatric leukemias remains a major challenge

Patients with multi-drug resistant leukemia are refractory to chemotherapy and have accumulated organ toxicities

New, well tolerated and effective agents are urgently needed

Relapsed leukemia is the third most common childhood cancer


Patients with multi-drug resistant leukemia are refractory to chemotherapy and have accumulated organ toxicities

New, well tolerated and effective agents are urgently needed

Clofarabine NDAClofarabine NDA

Steve Weitman, MD, PhDSteve Weitman, MD, PhD

Development OverviewClinical Study ResultsDevelopment OverviewClinical Study Results

ILEX Oncology, Inc.ILEX Oncology, Inc.

13

Clofarabine Development OverviewClofarabine Development Overview

Adult Phase I studies started in 1999

Pediatric Phase I studies started in 2000Striking activity in heavily pretreated population with acceptable toxicity profile

Compelling results in pediatric patients with an unmet medical need

Propelled development in pediatrics at a faster rate than adults

Increased the request for expanded access due to lack of alternative studies

Adult Phase I studies started in 1999

Pediatric Phase I studies started in 2000Striking activity in heavily pretreated population with acceptable toxicity profile

Compelling results in pediatric patients with an unmet medical need

Propelled development in pediatrics at a faster rate than adults

Increased the request for expanded access due to lack of alternative studies

14

Clofarabine Development TimelineClofarabine Development Timeline

Adult StudiesAdult

Studies

Pediatric Studies

Pediatric Studies

Phase ILeukemia

Phase I/ IICLO/ ARA-CAML, MDS

Phase IIAML

Phase IIAML, ALL, MDS, CML

Phase II/ IIICLO/ ARA-C

AMLIn Development

1999199919991999

2000200020002000

2001200120012001

2002200220022002

2003200320032003

2004200420042004

20052005

Phase IIAML

Phase ILeukemia Phase II

ALLCOG Phase II CLO/ ARA-C

AML, ALLIn Development

15

Phase I Pediatric ALL & AML Phase I Pediatric ALL & AML

Twenty-five patients

Dose levels from 11-70 mg/m2/day x 5

MTD 52 mg/m2/day IV

DLT was reversible increases in bilirubin and skin rash

ResponseCR 5/25 (20%)PR 3/25 (12%)

7 of 25 patients went to transplant

Twenty-five patients

Dose levels from 11-70 mg/m2/day x 5

MTD 52 mg/m2/day IV

DLT was reversible increases in bilirubin and skin rash

ResponseCR 5/25 (20%)PR 3/25 (12%)

7 of 25 patients went to transplant Jeha, et. al. Blood. 2004;103:784-789

16

Pivotal Pediatric ALL & AML Pivotal Pediatric ALL & AML

Planned Study DesignPrimary Endpoint is Overall Response Rate (CR+CRp)

Fleming 2 stage design - (40% response rate of interest was based on 1 to 2 prior regimens)

Current Clinical PracticePopulation was heavily pretreated, having highly resistant leukemia (up to 6 prior regimens)

Patients went to transplant before count recovery

The study size was expanded in collaboration with FDA to understand the true response rate

Planned Study DesignPrimary Endpoint is Overall Response Rate (CR+CRp)

Fleming 2 stage design - (40% response rate of interest was based on 1 to 2 prior regimens)

Current Clinical PracticePopulation was heavily pretreated, having highly resistant leukemia (up to 6 prior regimens)

Patients went to transplant before count recovery

The study size was expanded in collaboration with FDA to understand the true response rate

17

0

2

4

6

8

10

12

14

16

18

20

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 48

Pivotal Pediatric ALL Number of Unique Prior AgentsPivotal Pediatric ALL Number of Unique Prior Agents

Num

ber

of A

gent

s

Patients

Chemo Drugs Transplant TBI

18

Pivotal Pediatric AMLNumber of Unique Prior AgentsPivotal Pediatric AMLNumber of Unique Prior Agents

Num

ber

of A

gent

s

Patients

Chemo Drugs Transplant TBI

20042003200220012000

Post-Induction RegimenPost-Induction RegimenL-Asparaginase, Vincristine, CytarabineCyclophosphamide, Etoposide, Thioguanine

Transplant Prep RegimenTransplant Prep RegimenTBI, Thiotepa, Fludarabine Peripheral Blood SCT

4 Year Old AML Patient4 Year Old

AML Patient

Alivewith

NED

Induction Regimen 3Induction Regimen 3L-AsparaginaseCytarabine

Induction Regimen 4Induction Regimen 4Gemcitabine, TopotecanThiotepa, Vinorelbine

Induction Regimen 5Induction Regimen 5CytarabineIdarubicin

Induction Regimen 2Induction Regimen 2Etoposide , Daunorubicin, Cytarabine, Thioguanine

Clofarabine Cycle 1 Clofarabine Cycle 2 Clofarabine Cycle 3 Clofarabine Cycle 4 Clofarabine Cycle 5 Off Study Bone Marrow Transplant

ClofarabineClofarabine

Induction Regimen 1Induction Regimen 1Prednisone, Vincristine, Methotrexate

Safety and EfficacyPediatric LeukemiaSafety and EfficacyPediatric Leukemia

ALL & AMLALL & AML

21

NDA Efficacy/ Safety PopulationNDA Efficacy/ Safety Population

Efficacy data base N=84Efficacy data base N=84

Integrated safety data base N=113Integrated safety data base N=113

ALL AML

Pivotal Studies

49 35

22

Pivotal Study EndpointsPivotal Study Endpoints

Key Efficacy Endpoints: Independent Response Review Panel (IRRP) determined response: CR, CRp, PR

Duration of remission

Post-treatment transplants

Survival

Safety

Key Efficacy Endpoints: Independent Response Review Panel (IRRP) determined response: CR, CRp, PR

Duration of remission

Post-treatment transplants

Survival

Safety

Pivotal Pediatric ALL EfficacyPivotal Pediatric ALL Efficacy

24

Pivotal Pediatric ALL Characteristics of Study GroupPivotal Pediatric ALL Characteristics of Study Group

Number of Patients 49

Median Age in Years 12 (1 - 20)

Median # Prior Regimens 3 (2 - 6)

Patients Refractory to Most Recent Regimen 30 (61%)

Patients with Prior Transplants 15 (31%)

25

Pivotal Pediatric ALLIRRP Determined Best Objective ResponsePivotal Pediatric ALLIRRP Determined Best Objective Response

Number (%) 95% CI

Overall response (CR+CRp) (N=49)

10 (20%) 10 - 34%

Patients who achieved at least PR (N=49)

15 (31%) 18 - 45%

Patients who were refractory to most recent regimen (CR+CRp) (N=30)

5 (17%) 6 - 35%

26

0

25

50

75

100

0 5 10 15 20 25 30

Duration (Weeks)

Patie

nts

in R

emis

sion

(%)

Pivotal Pediatric ALLDuration of RemissionPivotal Pediatric ALLDuration of Remission

CR + CRp(N=10)Median 20.2 wks


CR + CRp + PR(N=15)Median 9.7 wks


Censored Value

27

Pivotal Pediatric ALLPost-Clofarabine TransplantsPivotal Pediatric ALLPost-Clofarabine Transplants

14% of patients went to transplant (7/49)

2 CR, 2 CRp, 2 PR, 1 NE

Median time to transplant was 32 days (range 16 - 77)

Median number cycles was 2 (range 2 - 3)

5 of 7 patients alive post-transplant


2 CR, 2 CRp, 2 PR, 1 NE


Median number cycles was 2 (range 2 - 3)


28

0

25

50

75

100

0 10 20 30 40 50 60 70

Survival (Weeks)

Patie

nt S

urvi

val (

%)

Pivotal Pediatric ALLOverall SurvivalPivotal Pediatric ALLOverall Survival



CR + CRp + PR(N=15)Median 42 wks


All Pts(N=49)Median 11.7 wks

All Pts(N=49)Median 11.7 wks

Censored Value

Pivotal Pediatric AML EfficacyPivotal Pediatric AML Efficacy

30

Pivotal Pediatric AML Characteristics of Study GroupPivotal Pediatric AML Characteristics of Study Group

Number of Patients 35

Median Age in Years 12 (2 - 22)

Median # Prior Regimens 3 (1 - 5)

Patients Refractory to Most Recent Regimen 22 (63%)

Patients with Prior Transplants 18 (51%)

31

Pivotal Pediatric AML IRRP Determined Best Objective ResponsePivotal Pediatric AML IRRP Determined Best Objective Response

Number (%) 95% CI

Overall response(CR+CRp) (N=35)

1 (3%) 0 - 15%

Patients who achieved at least PR(N=35)

9 (26%) 12 - 43%

Patients who were refractory to most recent regimen (CR+CRp, PR) (N=22)

4 (18%) 5 - 40%

32

0

25

50

75

100

0 10 20 30 40 50 60 70 80

Duration (Weeks)

Patie

nts

in R

emis

sion

(%)

Pivotal Pediatric AMLDuration of RemissionPivotal Pediatric AMLDuration of Remission



Censored Value

33

Pivotal Pediatric AMLPost-Clofarabine TransplantsPivotal Pediatric AMLPost-Clofarabine Transplants


1 CRp, 6 PR, 3 NE, 2 TF


Median number of cycles was 2 (range 1 - 5)



1 CRp, 6 PR, 3 NE, 2 TF


Median number of cycles was 2 (range 1 - 5)


34

0

25

50

75

100

0 10 20 30 40 50 60 70 80 90 100

Survival (Weeks)

Patie

nt S

urvi

val (

%)

Pivotal Pediatric AMLOverall SurvivalPivotal Pediatric AMLOverall Survival



All Pts(N=35)Median 21 wks

All Pts(N=35)Median 21 wks

Censored Value

35

Pivotal ALL & AML Efficacy Summary Pivotal ALL & AML Efficacy Summary

Recurrent pediatric acute leukemia is a substantial unmet medical need, especially for patients with AML

Impressive response rates with Clofarabine for pediatric patients with ALL and AML that has become cross-resistant to most currently available agents

The duration of remission was more than sufficient to allow patients with donors the opportunity to proceed to transplant

Long-term survival was observed in patients with ALL and AML who responded to Clofarabine

Recurrent pediatric acute leukemia is a substantial unmet medical need, especially for patients with AML

Impressive response rates with Clofarabine for pediatric patients with ALL and AML that has become cross-resistant to most currently available agents

The duration of remission was more than sufficient to allow patients with donors the opportunity to proceed to transplant

Long-term survival was observed in patients with ALL and AML who responded to Clofarabine

Integrated Safety AnalysisIntegrated Safety Analysis

37

All Grade 3 & 4 Adverse Events in > 10% of Pediatric Patients (N=113)

Integrated SafetyIntegrated Safety

54.0%

15.0% 15.0%6.2% 4.4%10.6%14.2%

6.2%7.1%7.1%0.9%

4.4%

0%

25%

50%

75%

100%

FebrileNeutropenia

Nausea Pyrexia Epistaxis HypotensionNOS

Sepsis Anorexia

Grade 3 Grade 4

38

Drug-Related Grade 3 & 4 Adverse Events in > 5% of Pediatric Patients (N=113)

Integrated SafetyIntegrated Safety

8.0%28.3%

8.8% 5.3%6.2%2.7%8.0%0.9%6.2%

0.9%

0%

25%

50%

75%

100%

FebrileNeutropenia

Nausea Pyrexia DiarrheaNOS

Neutropenia VomitingNOS

DermatitisNOS

Grade 3 Grade 4

39

All Grade 3 & 4 Hepato-Biliary/ Renal Lab AbnormalitiesAll Grade 3 & 4 Hepato-Biliary/ Renal Lab Abnormalities

Grade 3 Grade 4

37.3% 33.3%

11.6% 3.5% 1.0%1.8%3.6%

6.4%4.8%

0%

25%

50%

75%

100%

Elevated SGPT(ALT)

Elevated SGOT(AST)

Elevated TotalBilirubin

ElevatedCreatinine

Elevated AlkalinePhosphatase

40

Deaths During StudyDeaths During Study

ALL (N=67)

AML (N=46)

Disease Progression 7 (10%) 4 (9%)

Non Drug-related AE 6 (9%) 5 (11%)

Drug-related AE 3 (4%) 1 (2%)

Includes deaths within 30 days of last dose of study drug

41

Integrated Safety SummaryIntegrated Safety Summary

Heavily pretreated population

Many adverse events were consistent with underlying leukemia

Events are not unexpected for a cytotoxic agent

Most adverse events were reversible

Heavily pretreated population

Many adverse events were consistent with underlying leukemia

Events are not unexpected for a cytotoxic agent

Most adverse events were reversible

Stephen Sallan, MDStephen Sallan, MD

Clinician’s PerspectiveClinician’s Perspective

Dana-Farber Cancer Institute

43

Childhood Leukemia Childhood Leukemia

ALL 75 - 80% cured with multi-drug chemotherapy

AML 40 - 50% are cured


ALL 75 - 80% cured with multi-drug chemotherapy

AML 40 - 50% are cured


44

Survival in Pediatric LeukemiasSurvival in Pediatric Leukemias

0

20

40

60

80

100

1950 1960 1970 1980 1990 2000Year

Fiv

e Y

ear

Rel

ativ

e S

urvi

val R

ates

Kersey, Blood. 1997; 90(11):4243-4251

ALLALL

AMLAML

45

CR After Single Agents in Childhood ALLCR After Single Agents in Childhood ALLAdapted from Holland and Frei Cancer Medicine 1974

De Novo ALL CR

6-Mercaptopurine 25%

Methotrexate 20%

Cytarabine 30%

Multi-drug Resistant ALL CR+CRp

Clofarabine 20%

46

What Impresses Me As A ClinicianWhat Impresses Me As A Clinician

ALL Clofarabine results

1 in 5 children with multi-drug resistant ALL achieved a CR, affording them a transplant option

AML Clofarabine results

1 in 3 children with multi-drug resistant AML went to transplant

Transplant is the curative therapeutic option in drug-resistant childhood ALL and AML

ALL Clofarabine results

1 in 5 children with multi-drug resistant ALL achieved a CR, affording them a transplant option

AML Clofarabine results

1 in 3 children with multi-drug resistant AML went to transplant

Transplant is the curative therapeutic option in drug-resistant childhood ALL and AML

47

What Impresses Me As A ClinicianWhat Impresses Me As A Clinician

Clofarabine is Well Tolerated

No overlapping toxicities

Clofarabine provides Clinical Benefit

In a heterogeneous population

No meaningful Alternatives

Clofarabine is Well Tolerated

No overlapping toxicities

Clofarabine provides Clinical Benefit

In a heterogeneous population

No meaningful Alternatives

Commitment to Pediatric Clinical DevelopmentCommitment to Pediatric Clinical Development

Steve Weitman, MD, PhDSteve Weitman, MD, PhD

ILEX Oncology, Inc.ILEX Oncology, Inc.

49


This represents a new paradigm in pediatric drug developmentThe sponsor commits to further develop this drug in children:

Continue survival follow-up on pivotal studiesMoving to less heavily pretreated ALL and AML patientsProceed to a randomized study in pediatric patientsOur commitment includes working closely with the Children’s Oncology Group and CTEP

This represents a new paradigm in pediatric drug developmentThe sponsor commits to further develop this drug in children:

Continue survival follow-up on pivotal studiesMoving to less heavily pretreated ALL and AML patientsProceed to a randomized study in pediatric patientsOur commitment includes working closely with the Children’s Oncology Group and CTEP

50


Children’s Oncology Group (COG)/ CTEPAML Ara-C/Clofarabine Combination Study

First relapsed patients

Study chairs: Razzouk and Cooper

ALL Cytoxan/Clofarabine and Etoposide/Clofarabine Combination Study

– Second relapsed patients– Study chair: Hijiya

Children’s Oncology Group (COG)/ CTEPAML Ara-C/Clofarabine Combination Study

First relapsed patients

Study chairs: Razzouk and Cooper

ALL Cytoxan/Clofarabine and Etoposide/Clofarabine Combination Study

– Second relapsed patients– Study chair: Hijiya

51

Commitment toAdult Clinical Development ProgramCommitment toAdult Clinical Development Program

ObjectivesFocused on AML and MDSCombination studies with Ara-CInterest in elderly population of patients

Adult Leukemia StudiesCLO-141 Phase I/II Combination Ara-C/Clofarabine in AMLRandomized studies planned

Phase II/III Ara-C/Clofarabine in elderly patients with De Novo AMLPhase II/III Ara-C/Clofarabine in non-elderly adult patients with relapsed AML

Adult Development Discussion with FDA Ongoing

ObjectivesFocused on AML and MDSCombination studies with Ara-CInterest in elderly population of patients

Adult Leukemia StudiesCLO-141 Phase I/II Combination Ara-C/Clofarabine in AMLRandomized studies planned

Phase II/III Ara-C/Clofarabine in elderly patients with De Novo AMLPhase II/III Ara-C/Clofarabine in non-elderly adult patients with relapsed AML

Adult Development Discussion with FDA Ongoing

52

Overall Risk/ Benefit of Clofarabine inPediatric LeukemiaOverall Risk/ Benefit of Clofarabine inPediatric Leukemia

Acceptable safety profile in this heavily pre-treated patient populationImpressive benefits

Provided meaningful clinical response and cytoreduction (CR, CRp, and PR) Overall, 23% of patients proceeded to transplant (19/84)

14% of patients with ALL34% of patients with AML

Patients alive at data cutoff - ALL 22%, AML 26% (Median follow-up 29 weeks)

Meets an urgent unmet medical need in highly resistant pediatric leukemia

Acceptable safety profile in this heavily pre-treated patient populationImpressive benefits

Provided meaningful clinical response and cytoreduction (CR, CRp, and PR) Overall, 23% of patients proceeded to transplant (19/84)

14% of patients with ALL34% of patients with AML

Patients alive at data cutoff - ALL 22%, AML 26% (Median follow-up 29 weeks)

Meets an urgent unmet medical need in highly resistant pediatric leukemia



December 1, 2004


December 1, 2004

Documents

Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004 Pediatric Acute Leukemia December 1, 2004