Preliminary Results from a Phase 2 Study of ARQ 197 in Patients with Microphthalmia Transcription Factor Family (MiT) Associated Tumors Andrew Wagner 1 *, George Demetri 1 , Edwin Choy 2 , Alberto Pappo 3 , Steven DuBois 4 , James Geller 5 , Lee Rosen 6 , Neil Senzer 7 , Karen Albritton 1 , Feng Chai 8 , Dora Ferrari 8 , John Goldberg 9 * 1 Dana Farber Cancer Institute, Boston, MA; 2 Massachusetts General Hospital, Boston, MA; 3 Texas Children's Cancer Center, Houston TX; 4 University of California San Francisco Medical Center, San Francisco, CA; 5 Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 6 Premiere Oncology, Santa Monica, CA; 7 Mary Crowley Medical Research Center, Dallas, TX; 8 ArQule, Inc., Woburn, MA ; 9 University of Miami Miller School of Medicine, Miami, FL * These authors contributed equally to the study Sponsored by ArQule, Inc.
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Preliminary Results from aPhase 2 Study of ARQ 197
in Patients withMicrophthalmia Transcription
Factor Family (MiT) Associated Tumors
Andrew Wagner1*, George Demetri1, Edwin Choy2, Alberto Pappo3, Steven DuBois4, James Geller5, Lee
Rosen6, Neil Senzer7, Karen Albritton1, Feng Chai8, Dora Ferrari8, John Goldberg9*
1Dana Farber Cancer Institute, Boston, MA; 2Massachusetts General Hospital, Boston, MA; 3Texas Children's Cancer Center, Houston TX; 4University of California San Francisco Medical
Center, San Francisco, CA; 5Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 6Premiere Oncology, Santa Monica, CA; 7Mary Crowley Medical Research Center, Dallas, TX;
8ArQule, Inc., Woburn, MA ; 9University of Miami Miller School of Medicine, Miami, FL
* These authors contributed equally to the study
Sponsored by ArQule, Inc.
Background – MiT Associated Tumors
• Include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS) and Xp11.2-translocated renal cell carcinoma (tRCC)
• Associated with dysregulation of a related group of transcription factors including MITF, TFE3 and TFEB
• Generally resistant to all conventional systemic therapies
Members of the MiT family of transcription factors are oncogenes
Mechanism is dysregulated expression through amplification or translocation
•MITF targeted by EWS-ATF1 in CCS•MITF amplified in melanoma•TFE3 translocated: ASPS, tRCC•TFEB translocated: tRCC
MITF~TFE3~TFEB
I. Davis/D. Fisher J. Fletcher M. Ladanyi L. Garraway/W. Sellers
Transcription Factors are Notoriously Poor Drug Targets
“Drugable” downstream gene products?
MET is a transcriptional target of MiT family proteins
J Biol Chem 2006
Cancer Res 2007
MET and HGF are Highly Expressed in Primary Clear Cell Sarcoma Tumors
Data from Segal et al J. Clin Oncol 2003Slide courtesy IJ Davis
Starved 501melmRNA (PCR) HGF ELISA
Clear Cell Sarcoma Cells Express Active HGF
Ian Davis/David Fisher
ARQ 197
METKi for MET ~ 350 nM
IC50s: CAMKII ~ 10 M
Flt4 ~ 16 M
PAK3 ~ 6.6 M
Pim-1 33% inhibition @ 10 M
• Selective, non-ATP competitive inhibitor of MET
Ki or IC50• ARQ 197 demonstrates a favorable safety profile and preliminary anti-cancer activity in Phase 1 studies
Phosphoc-MET
c-MET
ARQ 197 (M): 0 0 1 3
rhHGF (100 ng/ml): - + + +
CCS292
-actin
ARQ 197 Inhibits Phospho-c-MET in CCS292 Cell Line
CCS292 cell line
0
50
100
0.0001 0.001 0.01 0.1 1 10 100
ARQ 197 (M)
Cell S
urv
ival (%
)
IC50 = 0.2 M
CCS292 cells were seeded in 96-well plates at 5,000 cells/well overnight in medium with 10% FBS. The next day, cells were treated with increasing concentrations of compound for 72 hours at 37° C. After addition of MTS reagents, the results were quantitated by spectrophotometry at = 490 nm and the GI50 was determined.
GI50 ~ 200 nM
CCS292 cells courtesy of Jonathan Fletcher
Study Design• Multi-center, single arm, two-stage
Phase 2 trial of ARQ 197 in patients with MiT Associated Tumors
• Objectives– Determine the ORR in patients treated with ARQ 197– Evaluate PFS in patients treated with ARQ 197– Evaluate 6-month and 1-year OS rates in patients treated with ARQ 197– Further characterize the safety of ARQ 197 in adolescent and young adult patients
with MiT tumors
Inclusion Criteria
• Tumor types: CCS, ASPS and tRCC
• Patient age: ≥ 13 years
• Patients with treated CNS metastases eligible if stable for ≥ 3 months and no neurologic symptoms
• No limitation on number of prior therapies
• Sufficient organ function
Methods
• Oral administration twice daily• Continuous dosing over 28-day cycles• Dosing initially 120 mg BID, then
amended to 360 mg BID– 18 patients on 120 mg BID
– 8 patients escalated from 120 to 360 mg BID
– 15 patients on 360 mg BID
• Tumor assessment by RECIST at 8-week intervals
Enrollment Status
0
5
10
15
20
25
30
35
40
Cu
mu
lati
ve E
nro
llmen
t
Month and Year
Demographics
CCS
(N=9)
ASPS
(N=23)
RCC
(N=9)
Total
(N=41)
Age*, mean 30.0 25.0 31.3 27.5
SexF 4 (44%) 16 (70%) 7 (78%) 27 (66%)
M 5 (56%) 7 (30%) 2 (22%) 14 (34%)
ECOG 0 5 (56%) 12 (52%) 6 (67%) 23 (56%)
1 4 (44%) 11 (48%) 3 (33%) 18 (44%)
Prior drug Rx, median (range) 1 (0-3) 1 (0-9) 0 (0-6) 1 (0-9)
Prior radiation, median (range)
1 (0-7) 1 (0-7) 0 (0-2) 1 (0-7)
Prior surgery median (range) 1 (0-6) 1 (0-17) 1 (0-5) 1 (0-17)