Phase II Study of Dasatinib in Advanced Sarcomas

SARC009Sarcoma PI: Scott Schuetze

GIST PI: Jon TrentRegistration and eCRF: CRAB, Seattle

Drug Supply: Bristol-Myers Squibb

SARC: November 13, 2008

Dasatinib

Small molecule inhibitor of src-family kinases, c-kit and PDGFR

Preclinical data suggested activity in Ewings & osteosarcoma in cell lines

Lack of activity in PPTP pediatric tumor panel Preclinical data suggests activity in GIST kit and

PDGFR mutants not responsive to imatinib

Dasatinib study objectives

Primary Evaluate clinical benefit rate = Choi response

or lack of progression for >6 months

Secondary Evaluate 2 and 5 year survival rates Assess clinical and laboratory toxicities Collect tumor for tissue microarray Collect blood samples for drug level and

functional inhibition of SRC phosphorylation

Patient Eligibility Measurable disease Age > 13 years weight > 50 kg ECOG 0-2 ANC > 1,500, Plt > 75,000 Creatinine < 2x ULN Serum calcium, magnesium and potassium > LLN Pt/PTT < 1.5 x ULN QTc interval < 450 msec LVEF > 45% (if prior treatment with anthracycline)

Exclusion/prohibitions

Disease curable by multidisciplinary management

Anti-platelet agents Anticoagulants Medications that prolong QT Active cardiac disease within 6 months Antacids – PPI, H-2 blockers IV bisphosphonates CYP 3A4/5 inducers/inhibitors

Treatment Plan

Tumor tissue submitted to UM (mandatory – all sites) Negative pregnancy test prior to starting drug (for

women of childbearing potential) CBC weekly 1st month, then monthly Serum chemistries including magnesium monthly H&P monthly ECG baseline & after 1st cycle Serum sample pre and post dose (selected sites) Response assessment every 2 months +/- 1 week – on

time reporting of response essential

SARC009: Imaging

Imaging every 8 weeks +/- 1 week, same method as baseline

Target lesions at least twice the size of slice thickness on CT

Target lesions on MRI should be at least 1cm Size = sum of greatest dimension of targets Density (CT only) = sum of average density of

targets

Choi criteria

CR = complete disappearance, no new lesions PR = >10% reduction in size or >15% decrease

in density Stable = neither CR, PR or PD PD = >10% increase in size but not >15%

decrease in density, or new lesions >1cm, or unequivocal progression of non-target lesions, or clinical deterioration from sarcoma

Dose Adjustment

Dasatinib dosing scheme 70 mg bid starting dose 50 mg bid level -1 100 mg once daily level -2

Intolerable grade 2 event, reduce dose without interruption

Significant non-hematologic grade 3 event, hold dose until grade 1 and then restart at reduced dose

Grade 4 non-hematologic event, hold dose until grade 1 and then restart at reduced dose

Grade 3 or 4 neutropenia or thrombocytopenia, hold dose until grade 1 and then restart at reduced dose

Correlative studies

Sub-type specific tissue microarrays – stored at UM, SARC sites will have access

Plasma sample obtained 2 hours after am dose 2-4 weeks after starting, store -20C or below – collection kits provided by SARC

PBMC lysate from sample pre and post am dasatinib dose 2-4 weeks after starting, store -70C or lower – collection kits provided by SARC

SARC009: enrollment by site

UM 39 Penn 21 MD Anderson 11 MGH 15 DFCI 14 City of Hope 19 Fox Chase 17 Stanford 17 Kootenai 16

Johns Hopkins 7

Indiana 6 Emory 8 U Pitt 5 WCI 4 SOC 3 Nebraska 2 Cedars-Sinai 2 Arkansas 1

SARC009: accrual by month

Protocol Accrual to SARC009 Dasatinib (N=207)data as of October 31, 2008

3

6

11

64

8 8

1210

19

57

9

26

1315

29

16

02468

10121416182022242628303234

May07

Jun07

Jul07

Aug07

Sep07

Oct07

Nov07

Dec07

Jan08

Feb08

Mar08

Apr08

May08

Jun08

Jul08

Aug08

Sep08

Oct08

Month/Year of Accrual

Frequency

SARC009: cumulative accrualProtocol Accrual to SARC009 (N=207)

data as of October 31, 2008

3 920 26 30

38 4658

6887 92 99

108

134147

162

191207

0

25

50

75

100

125

150

175

200

May0

7

Jul0

7

Sep0

7

Nov0

7

Jan0

8

Mar0

8

May0

8

Jul0

8

Sep0

8

Month/Year of Accrual

total patients

SARC 009: “Aggressive” sub-types

MFH – 34 OPEN Osteosarcoma – 27 On hold Leiomyosarcoma – 48 CLOSED Liposarcoma – 11 CLOSED Ewing’s family – 9 1st stage MPNST – 5 1st stage Rhabdomyosarcoma – 7 1st stage

N = min 9 to max 48 per stratum

SARC009: “Indolent” stratum

ASPS – 2 Chordoma – 8 Conventional chondrosarcoma – 19 Epithelioid sarcoma – 3 GCT – 0 Hemangiopericytoma – 10

N = 42 (maximum 116)

SARC009: ineligible

Desmoid/fibromatosis – 1 Extraskeletal myxoid chondrosarcoma - 1

SARC 009: GIST

Amendment approved May 1, 2008 Imatinib resistance/intolerance +/- sunitinib 22 enrolled to date

Patient demographics

Prior chemotherapy

yes - 76

no - 66

missing – 54

ECOG

0 – 79

1 – 75

2 – 7

missing - 35

Age

13-25y: 15

25-49y: 61

50-74y: 110

75+y: 10

Adverse events – all gradesRelatedNot Related

Cardiac Arrhythmia

Cardiac General

Coagulation

Death

Endocrine

Ocular/Visual

Constitutional symptoms

Gastrointestinal

Renal/Genitourinary

Blood/Bone Marrow

0 20 40 60 80 100

Adverse events – all grades

RelatedNot Related

Hemorrhage/Bleeding

Infection

Pulmonary/Upper Respiratory

Lymphatics

Metabolic/Laboratory

Musculoskeletal/Soft Tissue

Neurology

Pain

Dermatology/Skin

Sexual/Reproductive Function

0 20 40 60 80 100

Grade >3 AE

RelatedNot Related

Cardiac Arrhythmia

Cardiac General

Coagulation

Death

Endocrine

Ocular/Visual

Constitutional symptoms

Gastrointestinal

Renal/Genitourinary

Blood/Bone Marrow

0 20 40 60 80 100

Grade >3 AE

RelatedNot Related

Hemorrhage/Bleeding

Infection

Pulmonary/Upper Respiratory

Lymphatics

Metabolic/Laboratory

Musculoskeletal/Soft Tissue

Neurology

Pain

Dermatology/Skin

Sexual/Reproductive Function

0 20 40 60 80 100

Dasatinib-related SAEs

Cardiac Arrhythmia

Cardiac General

Coagulation

Death

Endocrine

Ocular/Visual

Constitutional symptoms

Gastrointestinal

Renal/Genitourinary

Blood/Bone Marrow

0 20 40 60 80 100

Dasatinib-related SAEs

Hemorrhage/Bleeding

Infection

Pulmonary/Upper Respiratory

Lymphatics

Metabolic/Laboratory

Musculoskeletal/Soft Tissue

Neurology

Pain

Dermatology/Skin

Sexual/Reproductive Function

0 20 40 60 80 100

Dasatinib dose

0

10

20

30

40

50

60

70

80

90

100

per

cen

t o

f p

atie

nts

70 mg BID 50 mg BID 100 mg QD

Reason off treatment

Progressive disease – 88 Clinical progression – 9 Patient withdrew – 9 Death – 12 AE, not related – 6 AE, related – 3 Physician decision – 0 Other - 2

SARC009: statistical design

Bayesian / dynamic analysis Start analysis after enrollment 9-10 per subtype “aggressive” subtypes - >25% response “indolent” group – 6 month PFS

> 50% = promising <30% = inactive

GIST - 6 month PFS >30% = promising <10% = inactive

Objective response MFHbaseline 4th cycle

Evaluable pts clinical benefit rate(CR/PR + > 6 month SD)

0

5

10

15

20

25

30

percent

MFH -

17

Leio

- 33

Osteo

- 13

Lipo -

10

Rhabdo

- 6

Ewings

- 5

MPNST -

3

MFH treatment duration

0 2 4 6 8 10

cycles

MFH

LMS – treatment duration

0 2 4 6 8 10 12 14

cycles

LMS

Osteosarcoma – treatment duration

0 2 4 6 8

cycles

Liposarcoma – treatment duration

0 2 4 6

cycles

Progression-free survival – “indolent” & GIST

Progression-Free SurvivalTreated patients with follow-upData as of October 27, 2008

0%

20%

40%

60%

80%

100%

0 3 6 9 12Months after Registration

GISTIndolent

Events / N3 / 10

21 / 36

6-MonthEstimate

58% (22,95)49% (32,65)

SARC009: summary Close to completing accrual in “aggressive “

sarcomas Preliminary results show activity in “MFH” Results in “indolent” sarcoma allow for continued

accrual GIST too soon to tell 1/3 require dose reduction AEs: hematologic, pulmonary, GI, constitutional,

pain Thanks to many investigators for rapid accrual! Thanks to SARC staff for excellent support!