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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.
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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
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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
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Transcription Factors are Notoriously Poor Drug Targets
“Drugable” downstream gene products?
MET is a transcriptional target of MiT family proteins
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J Biol Chem 2006
Cancer Res 2007
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MET and HGF are Highly Expressed in Primary Clear Cell Sarcoma Tumors
Data from Segal et al J. Clin Oncol 2003Slide courtesy IJ Davis
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Starved 501melmRNA (PCR) HGF ELISA
Clear Cell Sarcoma Cells Express Active HGF
Ian Davis/David Fisher
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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
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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
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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
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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
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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
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Enrollment Status
0
5
10
15
20
25
30
35
40
Cu
mu
lati
ve E
nro
llmen
t
Month and Year
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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)
Brain metastases Yes 0 (0%) 3 (13%) 1 (11%) 4 (10%)
No 9 (100%) 20 (87%) 8 (89%) 37 (90%)
*12 patients aged 11.3-18 years
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Number and Sites of Lesions at Baseline
• Median number of lesions at baseline: 5
• Location of lesions:Lesion location
CCS
(N=9)
ASPS
(N=23)
RCC
(N=9)
Total
(N=41)
Liver 2 8 4 14
Lung 8 23 5 36
Brain 0 3 1 4
Lymph node 3 9 4 16
Others 7 18 8 33
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Drug Safety (1)Most common (≥ 5%) drug-related adverse events (AEs)
AE TermNo. Patient (%) (N=41)
Total Grade ≥ 3 Fatigue 19 (46%) 0 Nausea 17 (41%) 0 Vomiting 14 (34%) 0 Sinus Bradycardia 8 (20%) 0 WBC count decreased 7 (17%) 1 (2%) Anemia 6 (15%) 2 (5%) Cough 4 (10%) 0 Diarrhea 4 (10%) 0 Headache 4 (10%) 0 Aspartate aminotransferase increased 3 (7%) 0
Neutrophil count decreased 3 (7%) 1 (2%) Dyspnea 3 (7%) 0 Rash 3 (7%) 0
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Drug Safety (2)
Drug-related serious AEs (SAEs)
SAE Term Dose (mg BID) Outcome
Grade 3 Febrile Neutropenia 360 Resolved within 1 week
Grade 4 Thrombocytopenia 360 Resolved within 2 weeks
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Efficacy (1)
36 patients evaluable for efficacy analysis
PR SD PDDisease
control rate#
ASPS (N=19) 0 (0%) 15 (79%) 4 (21%) 79%
CCS (N=8) 1 (12.5%) 3 (37.5%) 4 (50%) 50%
RCC (N=9)* 0 (0%) 3 (33%) 6 (67%) 33%
Total (N=36) 1 (3%) 21 (58%) 14 (39%) 61%
# Disease control rate = (PR+SD) / Number of evaluable patients X 100
* In 3 of 9 RCC patients, Xp11.2 translocations (TFE3 gene fusions) were not confirmed
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CT Scans of Patient 10 with CCSBaseline - April 7, 2008 Cycle 6 - October 6, 2008 (45.3% reduction)
29.4 mm 8.8 mm
17.3 mm
18.3 mm
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Kaplan-Meier TTP Curve ASPS
(Day)
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Kaplan-Meier TTP Curve CCS
(Day)
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Efficacy (2) Time to Progression (TTP)
Median (weeks)
12 Weeks 24 Weeks
ASPS (N=23) 37 85.4% 55.5%
CCS (N=9) 8 46.9% 31.2%
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Median Time on Treatment ARQ 197 vs. Prior Systematic Therapy
Tumor TypeWeeks on Treatment
ARQ 197 Prior Therapy
ASPS 16 (n=23) 9.5 (n=14*)
CCS 8 (n=9) 6.5 (n=6*)
TLA-RCC 8 (n=6) 4 (n=2*)
* Prior anticancer treatment history was not available for all patients.
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Conclusions
• ARQ 197 has demonstrated a favorable safety profile in both adult and pediatric patients
• Preliminary evidence of anti-cancer activity observed
• Enrollment at 360 mg BID is ongoing
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Thank You!
• Patients who participated in this study, their families, and referring physicians
• Co-investigators and clinical research teams at participating sites