Transcript 39313

Preliminary Results from a
Phase 2 Study of ARQ 197
in Patients with
Microphthalmia 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
MITF~TFE3~TFEB
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
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 2003
Slide courtesy IJ Davis
Clear Cell Sarcoma Cells
Express Active HGF
mRNA (PCR)
HGF ELISA
Ian Davis/David Fisher
Starved 501mel
ARQ 197
• Selective, non-ATP
competitive inhibitor of MET
Ki for MET
~ 350 nM
MET
IC50s: CAMKIId ~ 10 mM
Flt4
~ 16 mM
PAK3
~ 6.6 mM
Pim-1
33% inhibition @ 10 mM
• ARQ 197 demonstrates a
favorable safety profile and
preliminary anti-cancer
activity in Phase 1 studies
Ki or IC50
ARQ 197 Inhibits Phospho-c-MET in CCS292 Cell Line
CCS292
CCS292 cell line
rhHGF (100 ng/ml):
-
+
+
+
ARQ 197 (mM):
0
0
1
3
100
IC50 = 0.2 mM
Cell Survival (%)
Phospho
c-MET
50
0
0.0001
0.001
0.01
0.1
1
10
100
ARQ 197 (mM)
c-MET
GI50 ~ 200 nM
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 l = 490 nm and the GI50 was determined.
b-actin
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
35
30
25
20
15
10
Cumulative Enrollment
Enrollment Status
40
5
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Ja 08
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Month and Year
Demographics
CCS
(N=9)
ASPS
(N=23)
RCC
(N=9)
Total
(N=41)
30.0
25.0
31.3
27.5
F
4 (44%)
16 (70%)
7 (78%)
27 (66%)
M
5 (56%)
7 (30%)
2 (22%)
14 (34%)
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
1 (0-7)
1 (0-7)
0 (0-2)
1 (0-7)
1 (0-6)
1 (0-17)
1 (0-5)
1 (0-17)
0 (0%)
3 (13%)
1 (11%)
4 (10%)
9 (100%) 20 (87%)
8 (89%)
37 (90%)
Age*, mean
Sex
ECOG
(range)
Prior surgery median (range)
Brain metastases
Yes
No
*12 patients aged 11.3-18 years
Number and Sites of Lesions at Baseline
• Median number of lesions at baseline: 5
• Location of lesions:
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
Lesion location
Drug Safety (1)
Most common (≥ 5%) drug-related adverse events (AEs)
AE Term
Fatigue
Nausea
Vomiting
Sinus Bradycardia
WBC count decreased
Anemia
Cough
Diarrhea
Headache
Aspartate aminotransferase increased
Neutrophil count decreased
Dyspnea
Rash
No. Patient (%) (N=41)
Total
19 (46%)
17 (41%)
14 (34%)
8 (20%)
7 (17%)
6 (15%)
4 (10%)
4 (10%)
4 (10%)
3 (7%)
3 (7%)
3 (7%)
3 (7%)
Grade ≥ 3
0
0
0
0
1 (2%)
2 (5%)
0
0
0
0
1 (2%)
0
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
PD
Disease
control rate#
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%
ASPS (N=19)
#
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 CCS
Baseline - April 7, 2008
29.4 mm
Cycle 6 - October 6, 2008 (45.3% reduction)
8.8 mm
18.3 mm
17.3 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 Type
Weeks on Treatment
ARQ 197
Prior Therapy
16 (n=23)
9.5 (n=14*)
CCS
8 (n=9)
6.5 (n=6*)
TLA-RCC
8 (n=6)
4 (n=2*)
ASPS
* 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