DASATINIB (BMS-354825) FDA’s Oncologic Drugs Advisory Committee Meeting 2 June 2006.

DASATINIBDASATINIB(BMS-354825)(BMS-354825)

FDA’s Oncologic DrugsFDA’s Oncologic DrugsAdvisory Committee MeetingAdvisory Committee Meeting

2 June 20062 June 2006

IntroductionIntroductionDonna Morgan Murray, PhDDonna Morgan Murray, PhD

Bristol-Myers SquibbBristol-Myers SquibbGlobal Regulatory SciencesGlobal Regulatory Sciences

3

BMS PresentationBMS Presentation

IntroductionIntroduction ..………………..……………….. Donna Morgan Murray, PhDDonna Morgan Murray, PhDBMS,BMS, Global Regulatory SciencesGlobal Regulatory Sciences

Scientific RationaleScientific Rationale ……….………. Neil Shah, MD, PhDNeil Shah, MD, PhDUCSF School of MedicineUCSF School of Medicine

Clinical ProgramClinical Program………………………… Claude Nicaise, MDClaude Nicaise, MDBMS,BMS, Global DevelopmentGlobal Development

Clinical PerspectiveClinical Perspective ……...……... Hagop Kantarjian, MDHagop Kantarjian, MD MD Anderson Cancer CenterMD Anderson Cancer Center

ConclusionConclusion………………….…………………. Donna Morgan Murray, PhDDonna Morgan Murray, PhD

4

Consultants Available to the CommitteeConsultants Available to the Committee

Neil Shah, MD, PhDNeil Shah, MD, PhDAssistant ProfessorAssistant ProfessorDivision of Hematology/OncologyDivision of Hematology/OncologyDepartment of MedicineDepartment of MedicineUCSF School of MedicineUCSF School of MedicineSan Francisco, CASan Francisco, CA

Hagop Kantarjian, MDHagop Kantarjian, MD Chairman & ProfessorChairman & ProfessorLeukemia DepartmentLeukemia DepartmentThe University of TexasThe University of TexasMD Anderson Cancer CenterMD Anderson Cancer CenterHouston, TXHouston, TX

5

Medical Need for Therapeutic Options in CMLMedical Need for Therapeutic Options in CML

ChronicChronic AcceleratedAccelerated BlastBlast

Chronic Myeloid Leukemia (CML) is usually treated with Chronic Myeloid Leukemia (CML) is usually treated with imatinib, although resistance and intolerance developsimatinib, although resistance and intolerance develops

After imatinib failure, therapeutic options are limited After imatinib failure, therapeutic options are limited (e.g., (e.g., escalated doses of escalated doses of imatinib, hydroxyurea, interferon, imatinib, hydroxyurea, interferon, investigational agents, stem cell transplants)investigational agents, stem cell transplants)

Dasatinib offers a therapeutic option to patientsDasatinib offers a therapeutic option to patientsin all phases of CML after failure with imatinibin all phases of CML after failure with imatinib

6

Proposed Indications for Dasatinib Proposed Indications for Dasatinib

Treatment of adults with chronic, accelerated, or Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including resistance or intolerance to prior therapy including imatinibimatinib

Treatment of adults with Philadelphia Treatment of adults with Philadelphia chromosome‑positive (Ph+) acute lymphoblastic chromosome‑positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to myeloid leukemia with resistance or intolerance to prior therapy prior therapy

Scientific RationaleScientific RationaleNeil Shah, MD, PhDNeil Shah, MD, PhD

UCSF School of MedicineUCSF School of Medicine

8

Ph chromosomePh chromosome

BCR-ABLBCR-ABL (activated activated

tyrosine kinase)tyrosine kinase)

BCRBCR ABLABL

CMLCML

The Philadelphia (Ph) Chromosome The Philadelphia (Ph) Chromosome Leads to CMLLeads to CML

9

Loss of Response to Imatinib in CMLLoss of Response to Imatinib in CML

Chronic Phase – FrontlineChronic Phase – Frontline 16%16% (42 months)(42 months)

Chronic Phase – IFN failureChronic Phase – IFN failure 26%26%

Accelerated PhaseAccelerated Phase 73% (48 73% (48 months)months)

Blast CrisisBlast Crisis 95%95%

Rate of Relapse/Progression

Silver et al, 2004; Guilhot et al, 2004; Bhatia et al, 2002; Graham et al, 2002

For most imatinib-resistant or -intolerant patients, effective therapeutic options are severely limited

10

Clinical Resistance to Imatinib is AssociatedClinical Resistance to Imatinib is Associatedwith Restoration of BCR-ABL Kinase Activitywith Restoration of BCR-ABL Kinase Activity

MechanismsMechanisms

Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common)

Overproduction of BCR-ABL via genomic amplification

BCR-ABL-independent mechanismsBCR-ABL-independent mechanisms

11

E255K/V

M244V M351T

Y253H/F

E279K

F317L

E355G/D

F359C/V/D/I

H396R/PQ252H/R

E459K/Q

F486S

E450G/Q M388L

G250E/A/F

D276G

T277A

L387F/M

V379I

A397P E453G/KT315I/N

F311L/I

V289A

L298VL248V

E281A

L364I

G383D

E292V

x

Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004

P C A

Courtesy Tim Hughes

Map of Map of BCR-ABLBCR-ABL Kinase Domain Mutations Kinase Domain Mutations Associated with Clinical Resistance to ImatinibAssociated with Clinical Resistance to Imatinib

S417Y

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Dasatinib Inhibits Growth of 14/15 Imatinib-Dasatinib Inhibits Growth of 14/15 Imatinib-Resistant BCR-ABL-Expressing Ba/F3 Cell Lines Resistant BCR-ABL-Expressing Ba/F3 Cell Lines in in vitrovitro

Shah et al, Science, 2004

No

rmal

ized

cel

l n

um

be

r 48

ho

urs

of

dru

g e

xpo

sure

No

rmal

ized

cel

l n

um

be

r 48

ho

urs

of

dru

g e

xpo

sure

Concentration of dasatinib (nM)*Concentration of dasatinib (nM)*

0

0.2

0.4

0.6

0.8

1

1.2

0 0.5 2.5 5 25 50

T315I

Q252H

Ba/F3Bcr-AblE255K

M351T

M244V

G250E

Q252R

Y253F

Y253HE255V

F317L

E355G

F359V

H396R

F486S

T315I

Parental Ba/F3 cells

*Dasatinib is 300-400x more potent than imatinib in vitro*Dasatinib is 300-400x more potent than imatinib in vitro

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CMLimatinib-sensitive

(no mutation)

CMLimatinib-resistant

(BCR-ABL/M351T)Normal

veh

icle

5 n

M B

MS

-354

825

Dasatinib Selectively Inhibits BCR-ABL-dependent Hematopoiesis in vitro

Shah et al, Science 2004

Normal

veh

icle

5 n

M d

asat

inib

14

Summary of Scientific Rationale: Dasatinib for Summary of Scientific Rationale: Dasatinib for Imatinib-resistant and -intolerant CMLImatinib-resistant and -intolerant CML

Imatinib resistanceImatinib resistance

– Potently inhibits nearly all imatinib-resistant Potently inhibits nearly all imatinib-resistant BCR-ABL kinase domain mutationsBCR-ABL kinase domain mutations

– 300-400x more potent than imatinib at inhibiting 300-400x more potent than imatinib at inhibiting the activity of BCR-ABLthe activity of BCR-ABL

Imatinib intoleranceImatinib intolerance

– Structurally unrelated to imatinib, therefore, Structurally unrelated to imatinib, therefore, cross-intolerance not likelycross-intolerance not likely

Selectively inhibits the growth of BCR-ABL-positive Selectively inhibits the growth of BCR-ABL-positive hematopoietic progenitorshematopoietic progenitors

Clinical ProgramClinical ProgramClaude Nicaise, MDClaude Nicaise, MD

Bristol-Myers SquibbBristol-Myers SquibbGlobal DevelopmentGlobal Development

16

Clinical Program – Six Studies at 68 CentersClinical Program – Six Studies at 68 Centers

One Phase I Study (002)One Phase I Study (002) Dose escalation studyDose escalation study

– 15 mg to 180 mg QD and 25 mg to 70 mg BID in chronic phase15 mg to 180 mg QD and 25 mg to 70 mg BID in chronic phase

– 35 mg to 120 mg BID in advanced disease35 mg to 120 mg BID in advanced disease Intrapatient dose escalation / decrease to safe and effective doseIntrapatient dose escalation / decrease to safe and effective dose

Four Phase II Studies (013, 005, 006 and 015)Four Phase II Studies (013, 005, 006 and 015) Open label Open label Patients resistant or intolerant to imatinibPatients resistant or intolerant to imatinib

One Randomized Phase II Study (017)One Randomized Phase II Study (017) Open labelOpen label Control group: imatinib 800 mg/dayControl group: imatinib 800 mg/day Cross-over for lack of response or intoleranceCross-over for lack of response or intolerance

17

Rationale for 70 mg BID Dose SelectionRationale for 70 mg BID Dose Selection

Optimal drug exposureOptimal drug exposure

– Pharmacokinetic parametersPharmacokinetic parameters

• Cmax: 45 ng/mL (90 nM)Cmax: 45 ng/mL (90 nM)

– Pharmacodynamics and inhibition of pCRKLPharmacodynamics and inhibition of pCRKL

• ≈≈ 100% at doses 100% at doses 100 mg/day 100 mg/day

• BID > QDBID > QD

Effective dose in Phase I study (002) 70 mg BIDEffective dose in Phase I study (002) 70 mg BID

Acceptable safety in Phase I study (002)Acceptable safety in Phase I study (002)

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Imatinib ResistanceImatinib Resistance

Resistance at the maximum tolerated dose of imatinibResistance at the maximum tolerated dose of imatinib

Primary resistancePrimary resistance

– No complete hematologic response at 3 monthsNo complete hematologic response at 3 months

– No cytogenetic response at 6 monthsNo cytogenetic response at 6 months

– No major cytogenetic response at 1 yearNo major cytogenetic response at 1 year

Secondary resistanceSecondary resistance

– Loss of complete hematologic responseLoss of complete hematologic response

– Loss of major cytogenetic responseLoss of major cytogenetic response

– Progression to accelerated / blastProgression to accelerated / blast

19

Imatinib IntoleranceImatinib Intolerance

Imatinib toxicities leading to intoleranceImatinib toxicities leading to intolerance

– Grade 3-4 non-hematologic toxicityGrade 3-4 non-hematologic toxicity

– Grade 4 hematologic toxicity lasting more than Grade 4 hematologic toxicity lasting more than 7 days7 days

Patients who responded to imatinibPatients who responded to imatinib

– Developed intolerance while in responseDeveloped intolerance while in response

– Unable to resume therapyUnable to resume therapy

Patients who never responded to imatinibPatients who never responded to imatinib

– Unable to tolerate imatinib at a dose of at least Unable to tolerate imatinib at a dose of at least 400 mg400 mg

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Response CriteriaResponse CriteriaChronicChronic AdvancedAdvanced

Hematologic ResponseHematologic Response CompleteComplete CompleteCompleteNo EvidenceNo Evidenceof Leukemiaof Leukemia

WBCWBC ≤≤ ULNULN ≤≤ ULNULN ≤≤ ULNULN

Blasts/PromyelocytesBlasts/Promyelocytesin Peripheral Bloodin Peripheral Blood 00 00 00

Blasts in Bone MarrowBlasts in Bone Marrow N/AN/A ≤≤ 5%5% ≤≤ 5%5%

BasophilsBasophils < 20%< 20% < 20%< 20% < 20%< 20%

Myelocytes plus MetamyelocytesMyelocytes plus Metamyelocytesin Peripheral Bloodin Peripheral Blood < 5%< 5% < 5%< 5% < 5%< 5%

Platelets x 10Platelets x 1099/L/L < 450< 450 ≥≥ 100100 20 20 – – < 100< 100

Neutrophils x 10Neutrophils x 1099/L/L N/AN/A ≥≥ 11 0.5 0.5 –– < 1 < 1

Extramedullary DiseaseExtramedullary Disease NoNo NoNo NoNo

Cytogenetic ResponseCytogenetic ResponseComplete (CCyR)Complete (CCyR) Partial (PCyR)Partial (PCyR) Major (MCyR)Major (MCyR) 0% Ph+0% Ph+ 1% 1% –– 35% Ph+ 35% Ph+ CCyR + PCyRCCyR + PCyR

21

Patients in Clinical ProgramPatients in Clinical Program

No. of Patients in Phase I and IINo. of Patients in Phase I and II

002002 005005 006006 013013 015015 TotalTotal

ChronicChronic 4040 –– –– 186186 –– 226226

AcceleratedAccelerated 1111 107107 –– –– –– 118118

M. BlastM. Blast 2323 –– 7474 –– –– 9797

L. Blast / ALLL. Blast / ALL 1010 –– –– –– 7878 8888

TotalTotal 8484 107107 7474 186186 7878 529529

Randomized Trial: Study 017

36 patients (22 dasatinib and 14 imatinib)

22

Baseline CharacteristicsBaseline Characteristicsn (%) of Patientsn (%) of Patients

ChronicChronicN = 226N = 226

AcceleratedAcceleratedN = 118N = 118

M. BlastM. BlastN = 97N = 97

L. Blast/L. Blast/Ph+ ALLPh+ ALL

N = 88N = 88

Median Duration of CML Median Duration of CML (months)(months) 7070 8585 4848 2222

Prior ImatinibPrior Imatinib

ResistanceResistance 159 (70)159 (70) 106 (90)106 (90) 90 (93)90 (93) 80 (91)80 (91)

Dose >600 mg/dayDose >600 mg/day 123 (54)123 (54) 70 (59)70 (59) 49 (51)49 (51) 46 (52)46 (52)

Duration >3 years Duration >3 years 122 (54)122 (54) 79 (67)79 (67) 44 (45)44 (45) 12 (14)12 (14)

Prior Interferon Prior Interferon 167 (74)167 (74) 89 (75)89 (75) 53 (55)53 (55) 25 (28)25 (28)

Prior ChemotherapyPrior Chemotherapy 101 (45)101 (45) 76 (64)76 (64) 64 (66)64 (66) 75 (85)75 (85)

Prior Stem Cell TransplantPrior Stem Cell Transplant 19 (8)19 (8) 19 (16)19 (16) 14 (14)14 (14) 34 (39)34 (39)

BCR-ABL Mutations BCR-ABL Mutations 113 (50)113 (50) 64 (54)64 (54) 40 (41)40 (41) 43 (49)43 (49)

Platelets <100 x 10Platelets <100 x 1099/L/L 16 (7)16 (7) 47 (40)47 (40) 70 (72)70 (72) 65 (74)65 (74)

Efficacy in Efficacy in Chronic Phase CMLChronic Phase CML

Studies 002, 013 and 017Studies 002, 013 and 017

24

Chronic Phase CMLChronic Phase CML

Efficacy in Imatinib-resistant PatientsEfficacy in Imatinib-resistant Patients

n (%) of Patientsn (%) of Patients

Study 002Study 002N = 32N = 32

Study 013Study 013N = 127N = 127

Hematologic ResponseHematologic Response

Complete (CHR)Complete (CHR) 29 (91)29 (91) 111 (87)111 (87)

Cytogenetic ResponseCytogenetic Response

Major (MCyR)Major (MCyR) 12 (38)12 (38) 40 (31)40 (31)

Complete (CCyR)Complete (CCyR) 9 (28)9 (28) 28 (22)28 (22)

Loss of CHRLoss of CHR 00 22

Loss of MCyRLoss of MCyR 00 00

25

Major Cytogenetic Response Rate inMajor Cytogenetic Response Rate inImatinib-resistant PatientsImatinib-resistant Patients

31%

38%

31%34% 35%36%

42%43%

0

5

10

15

20

25

30

35

40

45

50

Study 002 Study 013

All Resistant Patients Prior Interferon Imatinib >600 mg/day BCR-ABL Mutation

Per

cen

t R

esp

on

der

s

29 25 98 92 602832 127N =N =


26

Efficacy in Imatinib-intolerant PatientsEfficacy in Imatinib-intolerant Patients





Complete (CHR)Complete (CHR) 8 (100)8 (100) 57 (97)57 (97)




Loss of CHRLoss of CHR 00 00



27

Major Cytogenetic Response inMajor Cytogenetic Response inImatinib-intolerant PatientsImatinib-intolerant Patients

75 737569

0

10

20

30

40

50

60

70

80

90

100

Study 002 Study 013

All Intolerant Patients Prior Interferon

Per

cen

t R

esp

on

der

s

8N = 8 59 32


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002 INTCENSORED

002 RESCENSORED

013 INTCENSORED

013 RESCENSORED

002 INT N= 8 NO. PROGRESSED = 0 MEDIAN= . (95% CI= . - . )002 RES N= 32 NO. PROGRESSED = 3 MEDIAN= . (95% CI= . - . )013 INT N= 59 NO. PROGRESSED = 0 MEDIAN= . (95% CI= . - . )

013 RES N= 127 NO. PROGRESSED = 8 MEDIAN= . (95% CI= . - . )

PROGRAM SOURCE : /wwbdm/clin/proj/ca/180/odac/val/stats/efficacy/programs/eff_pfs002_START.sas RUN DATE: 19-Apr-2006 16:54

PRO

POR

TIO

N N

OT

PRO

GR

ESSE

D

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 2 4 6 8 10 12 14 16 18 20

Progression-free Survival Progression-free Survival P

rop

ort

ion

No

t P

rog

ress

ed

Months

002 Int

002 Res013 Res

013 Int

Censored+ + + +


IntolerantIntolerant ResistantResistant

NN ProgressionProgression NN ProgressionProgression

Study 002Study 002 88 00 3232 33

Study 013Study 013 5959 00 127127 88

29

Preliminary Data of the Randomized Study 017Preliminary Data of the Randomized Study 017n (%) of Patientsn (%) of Patients

DasatinibDasatinibN = 22N = 22

ImatinibImatinibN = 14N = 14

Baseline CharacteristicsBaseline Characteristics

Prior Imatinib 600 mg/dayPrior Imatinib 600 mg/day 16 (73)16 (73) 12 (86)12 (86)

Prior InterferonPrior Interferon 14 (64)14 (64) 11 (79)11 (79)

BCR-ABL MutationsBCR-ABL Mutations 10 (45)10 (45) 1 (7)1 (7)

EfficacyEfficacy

Complete Hematologic ResponseComplete Hematologic Response 21 (95)21 (95) 13 (93)13 (93)

Major Cytogenetic ResponseMajor Cytogenetic Response 10 (45)10 (45) 3 (21)3 (21)

Complete Cytogenetic ResponseComplete Cytogenetic Response 7 (32)7 (32) 1 (7)1 (7)

CrossoverCrossover 2 (9)2 (9) 11 (79)11 (79)


Efficacy in Efficacy in Accelerated Phase CMLAccelerated Phase CML

Studies 002 and 005Studies 002 and 005

31

Efficacy Results Efficacy Results



Study 005Study 005N = 107N = 107


Major (MaHR)Major (MaHR) 6 (55)6 (55) 63 (59) 63 (59)

Complete (CHR)Complete (CHR) 5 (45)5 (45) 35 (33) 35 (33)

No Evidence of LeukemiaNo Evidence of Leukemia 1 (9)1 (9) 28 (26) 28 (26)




Loss of MaHRLoss of MaHR 0 0 1 1


Accelerated Phase CMLAccelerated Phase CML

32

002CENSORED

005CENSORED

002 N= 11 NO. PROGRESSED = 4 MEDIAN= . (95% CI= 4.8- . )005 N= 107 NO. PROGRESSED = 15 MEDIAN= . (95% CI= . - . )


PR

OP

OR

TIO

N N

OT

PR

OG

RE

SS

ED

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 2 4 6 8 10 12 14

Progression-free SurvivalProgression-free SurvivalP

rop

ort

ion

No

t P

rog

ress

ed

Months

Accelerated Phase CMLAccelerated Phase CML

NN ProgressionProgression

Study 005Study 005 107107 1515Study 002Study 002 1111 44

002

005

Censored+ +

Efficacy in Efficacy in Myeloid Blast CrisisMyeloid Blast Crisis


34

Efficacy Results Efficacy Results





Major (MaHR)Major (MaHR) 7 (30)7 (30) 24 (32)24 (32)

Complete (CHR)Complete (CHR) 3 (13)3 (13) 18 (24) 18 (24)

No Evidence of LeukemiaNo Evidence of Leukemia 4 (17)4 (17) 6 (8)6 (8)




Loss of MaHRLoss of MaHR 22 00


Myeloid Blast Phase CMLMyeloid Blast Phase CML

35

002CENSORED

006CENSORED

002 N= 23 NO. PROGRESSED = 16 MEDIAN= 4.4 (95% CI= 2.6- 7.8)006 N= 74 NO. PROGRESSED = 35 MEDIAN= . (95% CI= 3.4- . )


PR

OP

OR

TIO

N N

OT

PR

OG

RE

SS

ED

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 2 4 6 8 10 12


rop

ort

ion

No

t P

rog

ress

ed

Months

002

006

Censored+ +

Myeloid Blast Phase CMLMyeloid Blast Phase CML

NN ProgressionProgression

Study 002Study 002 2323 1616Study 006Study 006 7474 3535

Efficacy in Efficacy in Lymphoid Blast Crisis and Ph+ ALLLymphoid Blast Crisis and Ph+ ALL


37

Efficacy Results Efficacy Results n (%) of Patientsn (%) of Patients

Study 002Study 002 Study 015Study 015

L. Blast/Ph+ ALL L. Blast/Ph+ ALL N = 10N = 10

L. BlastL. BlastN = 42N = 42

Ph+ ALLPh+ ALLN = 36N = 36


Major (MaHR)Major (MaHR) 5 (50)5 (50) 13 (31)13 (31) 15 (42)15 (42)

Complete (CHR)Complete (CHR) 3 (30)3 (30) 11 (26)11 (26) 11 (31)11 (31)

No Evidence of LeukemiaNo Evidence of Leukemia 2 (20)2 (20) 2 (5)2 (5) 4 (11)4 (11)


Major (MCyR)Major (MCyR) 8 (80)8 (80) 21 (50)21 (50) 21 (58)21 (58)

Complete (CCyR)Complete (CCyR) 3 (30)3 (30) 18 (43)18 (43) 21 (58)21 (58)

Loss of MaHRLoss of MaHR 33 66 33

Loss of MCyRLoss of MCyR 66 1010 88

Lymphoid Blast Phase CML / Ph+ ALLLymphoid Blast Phase CML / Ph+ ALL

38

002 LB/ALLCENSORED

015 ALLCENSORED

015 LBCENSORED

002 LB/ALL N= 10 NO. PROGRESSED = 8 MEDIAN= 3.0 (95% CI= 1.4- 5.5)015 ALL N= 36 NO. PROGRESSED = 22 MEDIAN= 3.3 (95% CI= 1.1- 7.2)015 LB N= 42 NO. PROGRESSED = 30 MEDIAN= 2.8 (95% CI= 2.0- 4.3)


PR

OP

OR

TIO

N N

OT

PR

OG

RE

SS

ED

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 2 4 6 8 10


rop

ort

ion

No

t P

rog

ress

ed

Months

002 LB/ALL

015 LB015 ALL

Censored + + +

Lymphoid Blast Phase CML / Ph+ ALLLymphoid Blast Phase CML / Ph+ ALL

NN ProgressionProgression MedianMedian 95% CI95% CI

Study 002 LB/ALLStudy 002 LB/ALL 1010 88 3.03.0 1.4 – 5.51.4 – 5.5

Study 015 ALLStudy 015 ALL 3636 2222 3.33.3 1.1 – 7.21.1 – 7.2

Study 015 LBStudy 015 LB 4242 3030 2.82.8 2.0 – 4.32.0 – 4.3

39

H396R/PH396R/PF359C/I/VF359C/I/VE355GE355GM351TM351TT315IT315IE255K/VE255K/VY253H/FY253H/FG250EG250EM244VM244V

7/217/216/166/162/102/107/157/150/190/192/192/1910/2010/209/319/319/179/17MCyRMCyR

14/2114/218/168/166/106/1012/1512/150/190/198/198/1915/2015/2019/3119/3113/1713/17MaHRMaHR

P C A

Hematologic Responses by Mutation StatusHematologic Responses by Mutation Status

34 unique mutations9 amino acid substitutions account for 68% of all BCR-ABL mutations

40

Summary of EfficacySummary of Efficacy

Chronic Phase CML Chronic Phase CML

High rate of major cytogenetic response in imatinib-High rate of major cytogenetic response in imatinib-resistant and imatinib-intolerant patientsresistant and imatinib-intolerant patients

Durable responses extending beyond 1 yearDurable responses extending beyond 1 year

Progression-free survival at 6 months predictive ofProgression-free survival at 6 months predictive oflong-term benefitlong-term benefit

Advanced Disease (Accelerated, Blast, Ph+ ALL)Advanced Disease (Accelerated, Blast, Ph+ ALL)

High rate of major hematologic responsesHigh rate of major hematologic responses

Durable, complete responses in Ph+ ALLDurable, complete responses in Ph+ ALL

Long-term survivors identified at all stages including Long-term survivors identified at all stages including patients in blast transformationpatients in blast transformation

SafetySafety

42

Safety OverviewSafety Overview

Safety DatabaseSafety Database

511 leukemic patients treated with dasatinib BID511 leukemic patients treated with dasatinib BID

Minimum 8 months of follow-upMinimum 8 months of follow-up

Major FindingsMajor Findings

Myelosuppression, mostly thrombocytopeniaMyelosuppression, mostly thrombocytopenia

Fluid retention, including pleural effusionFluid retention, including pleural effusion

43

MyelosuppressionMyelosuppression





L. Blast / L. Blast / Ph+ ALLPh+ ALL

N = 88N = 88

Solid Solid TumorTumorN = 32N = 32

WBC <2.0 x 10WBC <2.0 x 1099/L/L 50 (24)50 (24) 71 (60)71 (60) 65 (68)65 (68) 60 (68)60 (68) 00

ANC <1.0 x 10ANC <1.0 x 1099/L/L 103 (50)103 (50) 92 (78)92 (78) 83 (86)83 (86) 67 (79)67 (79) 00

Platelets <50 x 10Platelets <50 x 1099/L/L 97 (47)97 (47) 97 (82)97 (82) 81 (84)81 (84) 72 (82)72 (82) 00

44

Time to Severe ThrombocytopeniaTime to Severe Thrombocytopenia

26

47

86 87

66

46

12 98 71 4

0

10

20

30

40

50

60

70

80

90

100

Chronic Accelerated Myeloid Blast Lymphoid Blast

<4 Weeks 4-8 Weeks >8 Weeks

Per

cen

t (%

)

45

Adverse Reactions RelatedAdverse Reactions Relatedto Myelosuppressionto Myelosuppression






N = 88N = 88TotalTotal

N = 511N = 511

GI HemorrhageGI Hemorrhage 8 (4)8 (4) 22 (19)22 (19) 14 (14)14 (14) 8 (9)8 (9) 52 (10)52 (10)

CNS HemorrhageCNS Hemorrhage 1 (<1)1 (<1) 00 00 2 (2)2 (2) 3 (1)3 (1)

Febrile NeutropeniaFebrile Neutropenia 3 (1)3 (1) 10 (8)10 (8) 5 (5)5 (5) 10 (11)10 (11) 28 (5)28 (5)

Severe InfectionsSevere Infections 5 (2)5 (2) 8 (7)8 (7) 6 (6)6 (6) 9 (10)9 (10) 28 (5)28 (5)

PneumoniaPneumonia 4 (2)4 (2) 5 (4)5 (4) 1 (1)1 (1) 4 (5)4 (5) 14 (3)14 (3)

SepsisSepsis 00 00 1 (1)1 (1) 1 (1)1 (1) 2 (<1)2 (<1)

AspergillosisAspergillosis 00 1 (1)1 (1) 00 00 1 (<1)1 (<1)

46

Management of MyelosuppressionManagement of Myelosuppression






N = 88N = 88

Transient Dose InterruptionTransient Dose Interruption 106 (51)106 (51) 55 (47)55 (47) 26 (27)26 (27) 11 (13)11 (13)

Median Duration (days)Median Duration (days) 1010 1414 77 1313

Dose ReductionDose Reduction 93 (45)93 (45) 44 (37)44 (37) 20 (21)20 (21) 5 (6)5 (6)

Platelet TransfusionPlatelet Transfusion 46 (22)46 (22) 71 (60)71 (60) 72 (74)72 (74) 54 (61)54 (61)

Red Cell TransfusionRed Cell Transfusion 63 (30)63 (30) 100 (85)100 (85) 87 (90)87 (90) 61 (69)61 (69)

HematopoieticHematopoieticGrowth FactorsGrowth Factors

32 (15)32 (15) 37 (31)37 (31) 26 (27)26 (27) 29 (33)29 (33)

DiscontinuationDiscontinuation 2 (1)2 (1) 1 (1)1 (1) 1 (1)1 (1) 1 (1)1 (1)

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Most Common Non-hematologicMost Common Non-hematologicAdverse ReactionsAdverse Reactions


Grade 1-4Grade 1-4 Grade 3-4Grade 3-4

Fluid RetentionFluid Retention 223 (44)223 (44) 42 (8)42 (8)

DiarrheaDiarrhea 179 (35)179 (35) 20 (4)20 (4)

RashRash 132 (26)132 (26) 7 (1)7 (1)

NauseaNausea 103 (20)103 (20) 5 (1)5 (1)

HeadacheHeadache 121 (24)121 (24) 5 (1)5 (1)

FatigueFatigue 108 (21)108 (21) 9 (2)9 (2)

DyspneaDyspnea 106 (21)106 (21) 19 (4)19 (4)

AstheniaAsthenia 82 (16)82 (16) 13 (3)13 (3)

Musculoskeletal painMusculoskeletal pain 77 (15)77 (15) 4 (1)4 (1)

VomitingVomiting 68 (13)68 (13) 4 (1)4 (1)

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Fluid RetentionFluid Retention


N = 511N = 511

Any Fluid RetentionAny Fluid Retention 223 (44)223 (44)

Superficial EdemaSuperficial Edema 144 (28)144 (28)

Pleural EffusionPleural Effusion 108 (21)108 (21)

OthersOthers

Pericardial EffusionPericardial Effusion 14 (3)14 (3)

Congestive Heart FailureCongestive Heart Failure 12 (2)12 (2)

Pulmonary EdemaPulmonary Edema 10 (2)10 (2)

Cardiac DysfunctionCardiac Dysfunction 7 (1)7 (1)

Pulmonary HypertensionPulmonary Hypertension 5 (1)5 (1)

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Pleural EffusionPleural Effusion





L. Blast/L. Blast/Ph+ ALLPh+ ALLN = 88N = 88

Drug-relatedDrug-related 38 (18)38 (18) 26 (22)26 (22) 29 (30)29 (30) 15 (17)15 (17)

Grade 3-4Grade 3-4 7 (3)7 (3) 3 (3)3 (3) 13 (13)13 (13) 2 (2)2 (2)

Time to Event Time to Event (days)(days) 7-3197-319 15-34315-343 1-2961-296 6-2476-247

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Management of Pleural EffusionManagement of Pleural Effusionn (%) of Patientsn (%) of Patients

with Eventswith Events

All Drug-related EventsAll Drug-related Events 108108

Medical InterventionMedical Intervention

DiureticsDiuretics 83 (77)83 (77)

CorticosteroidsCorticosteroids 37 (34)37 (34)

Dose InterruptionDose Interruption 48 (44)48 (44)

Dose ReductionDose Reduction 8 (7)8 (7)

Invasive ProceduresInvasive Procedures

ThoracentesisThoracentesis 19 (18)19 (18)

PleurodesisPleurodesis 1 (1)1 (1)

DiscontinuationDiscontinuation 4 (4)4 (4)

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Management of Other Events of Fluid RetentionManagement of Other Events of Fluid Retention

n (%) of Patientsn (%) of Patientswith Eventswith Events

All Drug-related EventsAll Drug-related Events 4444

Medical InterventionMedical Intervention

DiureticsDiuretics 34 (77)34 (77)

CorticosteroidsCorticosteroids 11 (25)11 (25)

Dose InterruptionDose Interruption 17 (39)17 (39)

Dose ReductionDose Reduction 4 (9)4 (9)

Invasive ProceduresInvasive Procedures

Pericardial windowPericardial window 2 (5)2 (5)

DiscontinuationDiscontinuation 6 (14)6 (14)

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Effect on Cardiac RepolarizationEffect on Cardiac Repolarization

Nonclinical evaluationNonclinical evaluation

– hERG IChERG IC5050: 14,300 : 14,300 nMnM

– No ECG change in telemetered monkeysNo ECG change in telemetered monkeys

Clinical findingsClinical findings

– Mean ∆ QTcF: 3–6 msecMean ∆ QTcF: 3–6 msec

QTc outlier analysis (serial ECGs in Phase II)QTc outlier analysis (serial ECGs in Phase II)

– QTcF: 3/446 >500 msec on Day 8QTcF: 3/446 >500 msec on Day 8

– ∆ ∆ QTcF: 13/441 >60 msec on Day 8QTcF: 13/441 >60 msec on Day 8

Adverse eventsAdverse events

– 9 AEs of QT prolongation9 AEs of QT prolongation

– No arrhythmia associated with QT prolongationNo arrhythmia associated with QT prolongation

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Laboratory AbnormalitiesLaboratory Abnormalities


Grade 1-4Grade 1-4 Grade 3-4Grade 3-4

ASTAST 321 (63)321 (63) 17 (3)17 (3)

ALTALT 296 (58)296 (58) 26 (5)26 (5)

BilirubinBilirubin 131 (26)131 (26) 16 (3)16 (3)

CreatinineCreatinine 175 (34)175 (34) 5 (1)5 (1)

↓ ↓ CaCa++++ 313 (62)313 (62) 50 (10)50 (10)

↓ ↓ MgMg++++ 175 (34)175 (34) 1 (<1)1 (<1)

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Dasatinib in Imatinib-intolerant PatientsDasatinib in Imatinib-intolerant Patients

94 intolerant patients94 intolerant patients

Similar safety profile to the entire populationSimilar safety profile to the entire population

– MyelosuppressionMyelosuppression

– Fluid retentionFluid retention

Minimal cross-intolerance with imatinibMinimal cross-intolerance with imatinib

– No recurrent hepatotoxicity or skin toxicityNo recurrent hepatotoxicity or skin toxicity

– Three patients developed the same grade 3 Three patients developed the same grade 3 toxicity on dasatinib (nausea, diarrhea, fatigue)toxicity on dasatinib (nausea, diarrhea, fatigue)

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Safety SummarySafety Summary

Myelosuppression Myelosuppression

– Predictable, frequently severePredictable, frequently severe

– Rarely complicated by severe bleeding or infectionRarely complicated by severe bleeding or infection

– Manageable by dose interruption, dose reduction and Manageable by dose interruption, dose reduction and occasionally by transfusionoccasionally by transfusion

Fluid retention including pleural effusionFluid retention including pleural effusion

– Common, likely related to PDGFR inhibitionCommon, likely related to PDGFR inhibition

– Managed with diuretics, corticosteroids, dose Managed with diuretics, corticosteroids, dose interruptions and, occasionally, invasive proceduresinterruptions and, occasionally, invasive procedures

Minimal hepatotoxicityMinimal hepatotoxicity

Other adverse events were usually mild to moderateOther adverse events were usually mild to moderate

Clinical PerspectiveClinical Perspective

Hagop M. Kantarjian, MDHagop M. Kantarjian, MD

Chairman & Professor, Leukemia DepartmentChairman & Professor, Leukemia DepartmentMD AndersonMD Anderson

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Chronic Phase CML – Imatinib-resistantChronic Phase CML – Imatinib-resistant

Poor prognosis after imatinib failurePoor prognosis after imatinib failure

– Few cytogenetic responses Few cytogenetic responses

– Poor survival: <2 years; <1 year with Poor survival: <2 years; <1 year with PP-loop -loop mutationsmutations

Limited treatment options: stem cell transplant, Limited treatment options: stem cell transplant, escalate imatinib, hydroxyurea, IFN-escalate imatinib, hydroxyurea, IFN-, , investigational agentsinvestigational agents

Major benefit with dasatinib:Major benefit with dasatinib:

– CHR 87% and MCyR >30%CHR 87% and MCyR >30%

– Duration of response > 1 yearDuration of response > 1 year

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Chronic Phase CML – Imatinib-intolerantChronic Phase CML – Imatinib-intolerant

Highest unmet medical needHighest unmet medical need– No benefit from targeted therapyNo benefit from targeted therapy

Imatinib intolerance uncommon, but often Imatinib intolerance uncommon, but often associated with resistanceassociated with resistance

67 patients with intolerance, mostly67 patients with intolerance, mostlynon-hematologic, treatednon-hematologic, treated– Hematologic and cytogenetic responses similar Hematologic and cytogenetic responses similar

to those achieved with imatinib post-interferonto those achieved with imatinib post-interferon– Responses durable; all patients progression-free Responses durable; all patients progression-free

(follow-up 6 to 20 months) (follow-up 6 to 20 months)

Minimal cross-intolerance Minimal cross-intolerance

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Accelerated Phase CML Post-imatinib FailureAccelerated Phase CML Post-imatinib Failure

Initial diagnosis of accelerated phase uncommon; Initial diagnosis of accelerated phase uncommon; most patients progress from chronic phase and are most patients progress from chronic phase and are imatinib-resistantimatinib-resistant

Poor prognosis: median survival <1 yrPoor prognosis: median survival <1 yr

– Limited options: hydroxyurea,Limited options: hydroxyurea,intensive chemotherapy +/- stem cell transplant, intensive chemotherapy +/- stem cell transplant, investigational agentsinvestigational agents

– No durable responsesNo durable responses

Dasatinib highly effectiveDasatinib highly effective

– High rates of durable hematologic and cytogenetic High rates of durable hematologic and cytogenetic response response

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Blast Phase CML Post-imatinib FailureBlast Phase CML Post-imatinib Failure

Almost all patients progressed to blast phase and Almost all patients progressed to blast phase and were imatinib resistantwere imatinib resistant

Very poor survival; rarely exceeds few monthsVery poor survival; rarely exceeds few months

– Most had prior chemotherapyMost had prior chemotherapy

– Limited options: intensive chemotherapy, Limited options: intensive chemotherapy, investigational therapyinvestigational therapy

Dasatinib induces durable responses unexpected Dasatinib induces durable responses unexpected with other therapeutic optionswith other therapeutic options

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Ph+ ALL Post-imatinib FailurePh+ ALL Post-imatinib Failure

Worst prognosis Worst prognosis

– No treatment options due to failure of prior No treatment options due to failure of prior therapies including chemotherapy and stem cell therapies including chemotherapy and stem cell transplanttransplant

– Expected survival less than 3 monthsExpected survival less than 3 months

Dasatinib highly effectiveDasatinib highly effective

– Durable complete hematologic and cytogenetic Durable complete hematologic and cytogenetic responses responses

– Duration of response > 4 monthsDuration of response > 4 months

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Overall Safety Overall Safety

Most important safety issues myelosuppression Most important safety issues myelosuppression and fluid retentionand fluid retention

Potentially severe, but manageable with early Potentially severe, but manageable with early interventionsinterventions

– Dose interruptionDose interruption

– Dose reductionDose reduction

– Non-invasive interventionsNon-invasive interventions

• Growth factors for myelosuppressionGrowth factors for myelosuppression

• Diuretics and steroids for fluid retentionDiuretics and steroids for fluid retention

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Dasatinib Benefit:Risk PotentialDasatinib Benefit:Risk Potential

Benefits patients with CML and Ph+ ALL who Benefits patients with CML and Ph+ ALL who have no other treatment optionshave no other treatment options

Highly effective in all CML phases post-Highly effective in all CML phases post-imatinib failureimatinib failure

Minimal cross-intolerance with imatinibMinimal cross-intolerance with imatinib

Myelosuppression predictable and manageableMyelosuppression predictable and manageable

Other toxicities (including pleural effusion) Other toxicities (including pleural effusion) manageable with early interventionmanageable with early intervention

ConclusionConclusionDonna Morgan Murray, PhDDonna Morgan Murray, PhD

Bristol-Myers SquibbBristol-Myers SquibbGlobal Regulatory SciencesGlobal Regulatory Sciences

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Proposed Indications for Dasatinib Proposed Indications for Dasatinib

Treatment of adults with chronic, accelerated, or Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) with blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including resistance or intolerance to prior therapy including imatinibimatinib

Treatment of adults with Philadelphia Treatment of adults with Philadelphia chromosome‑positive (Ph+) acute lymphoblastic chromosome‑positive (Ph+) acute lymphoblastic leukemia (ALL) and lymphoid blast chronic leukemia (ALL) and lymphoid blast chronic myeloid leukemia with resistance or intolerance to myeloid leukemia with resistance or intolerance to prior therapy prior therapy

DASATINIB (BMS-354825) FDA’s Oncologic Drugs Advisory Committee Meeting 2 June 2006.

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Transcript of DASATINIB (BMS-354825) FDA’s Oncologic Drugs Advisory Committee Meeting 2 June 2006.