Incidence of Hypophosphatemia Phos (Low) Number of Subjects (%) Total N = 511 Grade 0 277 (55) Grade 1 36 (7) Grade 2 100 (20) Grade 3 80 (16) Grade 4

Incidence of HypophosphatemiaIncidence of Hypophosphatemia

Phos (Low)Phos (Low)

Number of Subjects (%)Number of Subjects (%)

TotalTotalN = 511N = 511

Grade 0Grade 0 277 (55)277 (55)

Grade 1Grade 1 36 (7)




15a - 70

Patients with GI Bleeds and Proton Pump Patients with GI Bleeds and Proton Pump Inhibitors (PPI) – NDA SUInhibitors (PPI) – NDA SU

All GI bleedsAll GI bleeds 7979

PPI at anytime on-studyPPI at anytime on-study 6262(78%)(78%)

PPI at baselinePPI at baseline 1616(20%)(20%)

– Relevant medical historyRelevant medical history 44(5%)(5%)

12c - 6

Dasatinib Exposure: Dose ProportionalityDasatinib Exposure: Dose ProportionalityDasatinib Exposure vs Dose with B7D RegimenDasatinib Exposure vs Dose with B7D Regimen

Study 002 – Study 002 – MAD study; 84 subjects with CMLMAD study; 84 subjects with CML

At dose levels of 50–120 mg BID, the exposure increase At dose levels of 50–120 mg BID, the exposure increase was slightly more than dose proportional at steady statewas slightly more than dose proportional at steady state

RegimenRegimenAUCAUC(0-12h)(0-12h) (ng (ng·h/mL) ·h/mL)

Goemetric Mean (CV%)Goemetric Mean (CV%) Dose RatioDose Ratio AUC RatioAUC Ratio

50 mg BID50 mg BID 83 (32)83 (32) 11 11

70 mg BID70 mg BID 155 (54)155 (54) 1.41.4 1.81.8

90 mg BID90 mg BID 255 (58)255 (58) 1.81.8 3.03.0

120 mg BID120 mg BID 301 (66)301 (66) 2.42.4 3.63.6

25 - 1

Major Cytogenetic Responses in Imatinib-resistant Major Cytogenetic Responses in Imatinib-resistant Patients in Phase IPatients in Phase I

ScheduleSchedule

No. of RespondersNo. of RespondersTotal Daily DoseTotal Daily Dose

<100 mg<100 mg 100 mg100 mg 140 mg140 mg

BID (n = 15)BID (n = 15) 11 11 33

QD (n = 17)QD (n = 17) 11 44 22

Chronic Phase CML – Study 002Chronic Phase CML – Study 002

23 - 4

Mechanism of Action of Pleural EffusionMechanism of Action of Pleural Effusion

Likely related to the inhibition of PDGF-Likely related to the inhibition of PDGF-ββ

PDGF-PDGF-ββ regulates interstitial fluid homeostasis regulates interstitial fluid homeostasis in mouse modelin mouse model(Heuschel et al, PNAS 1999)(Heuschel et al, PNAS 1999)

Fluid retention described with other drugs Fluid retention described with other drugs known to inhibit PDGF-known to inhibit PDGF-ββ

– e.g. Imatinib, CDP860 (humanized antibody)e.g. Imatinib, CDP860 (humanized antibody)

13c - 2

Pretreatment CharacteristicsPretreatment Characteristicsn (%) of Patientsn (%) of Patients

DasatinibDasatinibN = 101N = 101

ImatinibImatinibN = 49N = 49

Median Duration of CML (months)Median Duration of CML (months) 6464 5252

Prior ImatinibPrior Imatinib

Dose = 600 mg/dayDose = 600 mg/day 62 (61)62 (61) 34 (69)34 (69)

Duration >3 years Duration >3 years 45 (45)45 (45) 15 (31)15 (31)

Major Cytogenetic ResponseMajor Cytogenetic Response 28 (28)28 (28) 14 (29)14 (29)

Prior Interferon Prior Interferon 74 (73)74 (73) 33 (67)33 (67)

BCR-ABL mutationsBCR-ABL mutations 42 (42)42 (42) 10 (20)10 (20)

Study 017Study 017

24 - 2

Patient DispositionPatient Disposition

n (%) of Patientsn (%) of Patients



DiscontinuationDiscontinuation 15 (15)15 (15) 37 (76)37 (76)

Reason for discontinuationReason for discontinuation

Progression / No responseProgression / No response 8 (8)8 (8) 27 (55)27 (55)

IntoleranceIntolerance 7 (7)7 (7) 9 (18)9 (18)

Non-complianceNon-compliance 00 1 (2)1 (2)

Study 017Study 017

24 - 3

EfficacyEfficacy

n (%) of Patientsn (%) of Patients



At 3 monthsAt 3 months


Complete Cytogenetic ResponseComplete Cytogenetic Response 21 (21)21 (21) 4 (8)4 (8)

At any time prior to cross overAt any time prior to cross over

Complete Hematologic ResponseComplete Hematologic Response 93 (92)93 (92) 40 (82)40 (82)


Complete Cytogenetic ResponseComplete Cytogenetic Response 27 (27)27 (27) 6 (12)6 (12)

Study 017Study 017

24 - 4

Major Cytogenetic Response at 3 MonthsMajor Cytogenetic Response at 3 Months

23%

35%39%

0%

21%24%

0

5

10

15

20

25

30

35

40

45

Prior Interferon Imatinib 600 mg/day No Prior CytogeneticResponse

Dasatinib Imatinib

Per

cen

t R

esp

on

der

s

63 34 153974 33N =N =

Study 017Study 017

24 - 5

DASATINIBCENSORED

IMATINIBCENSORED

DASATINIB N= 101 NO. FAILED = 15 MEDIAN= . (95% CI= . - . )IMATINIB N= 49 NO. FAILED = 37 MEDIAN= 3.5 (95% CI= 3.3- 3.8)

Time to Treatment failure

PROGRAM SOURCE : /wwbdm/clin/proj/ca/180/017/val/stats/120SAFETY/OVERALL/programs/eff_pfs_asco.sas RUN DATE: 11-May-2006 7:52

PRO

POR

TIO

N N

OT

FAIL

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

Time to Treatment FailureTime to Treatment FailureStudy 017Study 017

DasatinibDasatinib ImatinibImatinib

NN 101101 4949

Number FailedNumber Failed 1515 3737

MedianMedian 3.53.5

95% CI95% CI 3.3 - 3.83.3 - 3.8

Months

Dasatinib

Imatinib

Censored+ +

24 - 12

Non-Hematological Adverse EventsNon-Hematological Adverse Events



Fluid retentionFluid retention 25 (25)25 (25) 21 (43)21 (43)

Superficial edemaSuperficial edema 13 (13)13 (13) 20 (41)20 (41)

Pleural effusionPleural effusion 11 (11)11 (11) 00

DiarrheaDiarrhea 26 (26)26 (26) 14 (29)14 (29)

HeadacheHeadache 25 (25)25 (25) 4 (8)4 (8)

GI hemorrhageGI hemorrhage 2 (2)2 (2) 00

FatigueFatigue 28 (28)28 (28) 10 (20)10 (20)

RashRash 16 (16)16 (16) 8 (16)8 (16)

OtherOther 6 (6)6 (6) 2 (4)2 (4)

Study 017Study 017

24 - 7

MyelosuppressionMyelosuppression



WBC <2.0 x10WBC <2.0 x1099/L/L 18 (18)18 (18) 9 (18)9 (18)

ANC <1.0 x10ANC <1.0 x1099/L/L 58 (58)58 (58) 19 (38)19 (38)

Platelets <50 x10Platelets <50 x1099/L/L 54 (54)54 (54) 7 (14)7 (14)

Hemoglobin <8 g/dLHemoglobin <8 g/dL 9 (9)9 (9) 4 (8)4 (8)

Platelets transfusionPlatelets transfusion 13 (13)13 (13) 00

Red cell transfusionRed cell transfusion 17 (17)17 (17) 6 (12)6 (12)

Study 017Study 017

24 - 8

Documents

Incidence of Hypophosphatemia Phos (Low) Number of Subjects (%) Total N = 511 Grade 0 277 (55) Grade 1 36 (7) Grade 2 100 (20) Grade 3 80 (16) Grade 4