phase ii study of dasatinib (bms-354825) in advanced sarcomas and chordoma
DESCRIPTION
Phase II Study of Dasatinib (BMS-354825) in Advanced Sarcomas and Chordoma. Coordinating Center: U Michigan. Probability of response to imatinib (95% posterior credible intervals). Rationale for trial: extension of results from imatinib in sarcoma. - PowerPoint PPT PresentationTRANSCRIPT
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