phase ii study of dasatinib (bms-354825) in advanced sarcomas and chordoma

Phase II Study of Dasatinib Phase II Study of Dasatinib (BMS-354825) in Advanced (BMS-354825) in Advanced Sarcomas and ChordomaSarcomas and Chordoma

Coordinating Center: U MichiganCoordinating Center: U Michigan

Probability of response to imatinibProbability of response to imatinib(95% posterior credible intervals)(95% posterior credible intervals)

0.0 0.2 0.4 0.6 0.8 1.0

-12

-10

-8-6

-4-2

0.0 0.2 0.4 0.6 0.8 1.0

Angiosarcoma

Ewings

Fibrosarcoma

Leiomyosarcoma

Liposarcoma

MFH

Osteosarcoma

PNS

Rhabdomyosarcoma

Synovial

Desmoid

Rationale for trial:Rationale for trial:extension of results from extension of results from

imatinib in sarcomaimatinib in sarcoma 30% of liposarcomas and fibrosarcomas 30% of liposarcomas and fibrosarcomas

showed clinical benefit to gleevecshowed clinical benefit to gleevec 2 leiomyosarcomas, 2 MFH and 1 2 leiomyosarcomas, 2 MFH and 1

liposarcoma showed objective response liposarcoma showed objective response by RECISTby RECIST

Mechanism of response not knownMechanism of response not known C-kit and PDGFR mutations identified in C-kit and PDGFR mutations identified in

minority of sarcomasminority of sarcomas

Chordomas are affected byChordomas are affected byimatinib - ? inhibition of PDGFRimatinib - ? inhibition of PDGFR

pre post

From P.G. Casali et al

Role of src in cancerRole of src in cancer

V-Src oncogenic protein of V-Src oncogenic protein of Rous sarcoma virusRous sarcoma virus

Src kinases activated by Src kinases activated by receptor tyrosine kinasesreceptor tyrosine kinases

Src elevated expression found Src elevated expression found in many cancersin many cancers

May be involved in tissue May be involved in tissue invasion/metastasisinvasion/metastasis

Involved in osteoblast Involved in osteoblast biologybiology

C-SRC expression in STSC-SRC expression in STS

HistologyHistology NN 00 1+1+ 2+2+

LeiomyoLeiomyo 2525 33 1717 55

MFHMFH 2020 00 1515 55

LipoLipo 1616 22 1414 00

FibrosarcFibrosarc 1111 22 55 44

AngiosarcAngiosarc 1212 00 77 55

RhabdoRhabdo 1818 88 88 22

Antibody AP7718a (Abgent) 1:50

C-SRC expression in STSC-SRC expression in STS

0

10

20

30

40

50

60

70

80

90

100

Rhab

dom

yosa

rcom

a (n=

18)

Angi

osar

com

a(n

=12

)

Lipo

sarc

oma

(n=

16)

Mal

igna

nt F

ibro

usHi

stio

cyto

ma

(n=

20)

Gast

ro-In

test

inal

Stro

mal

Tum

or (n=

6)

Mal

igna

ntPe

riphe

ral N

erve

Shea

th T

umor

(n=

26)

Ewin

gs S

arco

ma

(n=

26)

Syno

vial

Sar

com

a (n=

21)

Leio

myo

sarc

oma

(n=

25)

Fibro

sarc

oma

(n=

11)

cSRC

IMM

UN

ORE

ACTI

VITY

2+

1+

Tissue microarray – 181 samples

DasatinibDasatinib

Small molecule inhibitor of src-family Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFRkinases (src, bcr-abl) and PDGFR

PDGFR inhibition requires higher doses PDGFR inhibition requires higher doses – IC– IC5050 30nM 30nM

Oral dosingOral dosing Short half-life Short half-life Overcomes resistance to gleevec in Overcomes resistance to gleevec in

CMLCML

Sarcoma study objectivesSarcoma study objectives

Evaluate clinical benefit rateEvaluate clinical benefit rate 4 and 6 month PFS4 and 6 month PFS Time to progressionTime to progression Objective response rate – confirmed CR and PRObjective response rate – confirmed CR and PR Assess clinical and laboratory toxicitiesAssess clinical and laboratory toxicities Characterize mutations in PDGFRCharacterize mutations in PDGFR Characterize expression levels of src in tumorCharacterize expression levels of src in tumor

Definition of clinical benefitDefinition of clinical benefit

SD

CR

PR

PD

Month 2

CR

PR

SD

PD

Month 6

SD

CR

PR

PD

Month 4

Proposed patient groupsProposed patient groups

Extraskeletal osteosarcomaExtraskeletal osteosarcoma FibrosarcomaFibrosarcoma Liposarcoma (not myxoid)Liposarcoma (not myxoid) MFHMFH OsteosarcomaOsteosarcoma RhabdomyosarcomaRhabdomyosarcoma Uterine leiomyosarcomaUterine leiomyosarcoma High-grade chondrosarcomaHigh-grade chondrosarcoma

ASPSASPS ChordomaChordoma Epithelioid sarcomaEpithelioid sarcoma GCTGCT HemangipericytomaHemangipericytoma Conventional Conventional

chondrosarcomachondrosarcoma

Faster growthFaster growth Slower growthSlower growth

PFS in phase II studies of previously PFS in phase II studies of previously treated soft tissue sarcomatreated soft tissue sarcoma

DrugDrug DiseaseDisease 3 mo PFS3 mo PFS 4 mo PFS4 mo PFS 6 mo PFS6 mo PFS

Gem/TaxGem/Tax LeiomyoLeiomyo 47%47%

ET-743ET-743 STSSTS 52%52% 29%29%

ET-743ET-743 STSSTS 44%44% 28%28%

TemodarTemodar STSSTS 42%42% 27%27%

TemodarTemodar STSSTS 40%40% 22%22%

9-NC9-NC STSSTS 26%26% 22%22%

AP23573AP23573 STS/boneSTS/bone 22%22%

GemGem STS/gistSTS/gist 15%15%

SU5416SU5416 STSSTS 8%8% 0%0%

ActiveActive STSSTS 39%39% 30%30% 14%14%

InactiveInactive STSSTS 21%21% 8%8%

PFS in phase II studies in untreated PFS in phase II studies in untreated soft tissue sarcomasoft tissue sarcoma

DrugDrug DiseaseDisease 6 mo PFS6 mo PFS

Doxo/avastinDoxo/avastin STSSTS 50%50%

GemGem STSSTS 56%56%

EpoBEpoB STSSTS 41%41%

DoxilDoxil STSSTS 22%22%

ET-743ET-743 STSSTS 24%24%

EORTC trialsEORTC trials STSSTS 40-55%40-55%

PFS in slow growth sarcomasPFS in slow growth sarcomas

DrugDrug DiseaseDisease 3 mo PFS3 mo PFS 6 mo PFS6 mo PFS

9-NC9-NC ChordomaChordoma 47%47% 33%33%

ABT-510ABT-510 ASPSASPS

DocetaxelDocetaxel Low-grade Low-grade STSSTS

30%30%

Proposed response threshholdsProposed response threshholds

Target clinical benefit rate at 6 months of at Target clinical benefit rate at 6 months of at least 20% in “faster growth” groupleast 20% in “faster growth” group

Target clinical benefit rate at 6 months of at Target clinical benefit rate at 6 months of at least 40% in “slower growth” groupleast 40% in “slower growth” group

Patient eligibilityPatient eligibility

Group 1: Advanced high-grade fibrosarcoma, Group 1: Advanced high-grade fibrosarcoma, uterine leiomyosarcoma, liposarcoma, MFH, uterine leiomyosarcoma, liposarcoma, MFH, rhabdomyosarcoma, osteosarcoma treated with rhabdomyosarcoma, osteosarcoma treated with 1 or more prior therapies1 or more prior therapies

Group 2: Unresectable or recurrent Group 2: Unresectable or recurrent chondrosarcoma, chordoma, epithelioid chondrosarcoma, chordoma, epithelioid sarcoma, alveolar soft part sarcoma, sarcoma, alveolar soft part sarcoma, hemangiopericytoma, GCThemangiopericytoma, GCT

Measurable diseaseMeasurable disease Progressive disease – for Group 1 patientsProgressive disease – for Group 1 patients

Treatment planTreatment plan

Archival tissue to be submitted for PDGFR Archival tissue to be submitted for PDGFR and c-src analysis (mandatory)and c-src analysis (mandatory)

Once-a-day dosing of dasatinib (starting dose Once-a-day dosing of dasatinib (starting dose pending results of current Phase I study)pending results of current Phase I study)

Response assessment every 2 months +/- 1 Response assessment every 2 months +/- 1 weekweek

Treat until progression or unmanageable Treat until progression or unmanageable toxicitytoxicity

Implementation timelineImplementation timeline

LOI approved by BMSLOI approved by BMS Protocol in developmentProtocol in development Submit to UM PRC/IRB in JanuarySubmit to UM PRC/IRB in January 4-6 month approval process4-6 month approval process Distribute to SARC sites after approvalDistribute to SARC sites after approval