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)

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

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

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

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

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

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

Kaplan-Meier TTP Curve ASPS

(Day)

Kaplan-Meier TTP Curve CCS

(Day)

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%

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.

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

Thank You!

• Patients who participated in this study, their families, and referring physicians

• Co-investigators and clinical research teams at participating sites