ACRIN 6687
A Phase 2, Multicenter Evaluation of 18F-Fluoride PET
as a Pharmacodynamic Biomarker
for Dasatinib, a Src Kinase Inhibitor, in Men With
Castration-Resistant
Prostate Cancer and Bone Metastases
Principal Investigators: Evan Y. Yu, MD and
David A. Mankoff, MD, PhD
Background
• ACRIN 6687 is a companion imaging protocol to accompany the
therapeutic protocol “Genomic Guided Therapy with Dasatinib
or Nilutamide in Metastatic Castration-Resistant Prostate
Cancer.” (Dr. Phillip Febbo) supported through the Department
of Defense and Bristol-Meyers Squibb
• Eligible patients currently enrolled in Dr. Febbo’s therapeutic
trial and receiving dasatinib undergo 18F-fluoride PET imaging.
– This includes patients genetically indicated to have tumors
with SRC microarray signatures who initial dasatinib-alone
treatment, as well as those patients with initial AR microarray
signatures who may crossover at the time of progression to
have dasatinib added to nilutamide.
AR Transcriptional Signature
Gene expression “Signature” to detect AR activity
Febbo et al, Urology (2005)
Probability of AR Activity
R1881
Metagene Score
Mendiratta et al, JCO (2009)
AR Transcriptional Signature
Neoadjuvant
No
Treatment
After
Castration
Metastatic CRPC
No
Treatment
Castration
Resistant
AR activity correponded
to tissue DHT levels
Data from Holzbelerlein et al. Am J Path (2004) and Stanbrough et al Cancer Res (2007).
Study Schema
18F-Fluoride
18F-Fluoride
PET
PET
PCCTC and ACRIN Collaboration
• Metastatic,
Castration
Resistant
Prostate Cancer
• Disease
Amenable to
Biopsy
• Castrate
Testosterone
Levels
B
i
o
p
s
y
A
R
A
c
t
i
v
i
t
y
Nilutamide
150 mg PO QD
Dasatinib
100 mg PO QD
P
r
o
g
r
e
s
s
i
o
n
18F-Fluoride
18F-Fluoride
PET
PET
Dasatinib
100 mg PO QD
Nilutamide
150 mg PO QD
P
r
o
g
r
e
s
s
i
o
n
Goals
• Potential Insight Gained From the Trial:
–
18F-fluoride
PET evaluation of an agent, such as
dasatinib, that is expected to affect both normal
bone and bone metastases
– Gain pharmacodynamic information with 18Ffluoride PET on the effects of dasatinib both on
normal bone and bone metastases
18F-fluoride
– Determine
whether
PET
has
prognostic and response biomarker potential for
patients with bone metastatic prostate cancer
Endpoints
• Primary Endpoint
– Determine if changes in regional fluoride incorporation,
measured by 18F-fluoride PET (SUV and Ki), occur in both
castration-resistant prostate cancer bone metastases and
normal bone as a response to treatment with dasatinib
• Secondary Endpoint:
– Determine if changes in 18F-fluoride transport (K1), an
indicator of blood flow, and therefore, an indirect marker of
angiogenesis, occur in both castration-resistant prostate
cancer bone metastases and normal bone as a response to
treatment with dasatinib
ACRIN 6687 Current Status
• Accrual to Treatment Trial
• Current Accrual: 54 (N= 60)
• 6687 Imaging Protocol
• Current Accrual: 12 (N=24)
• A total of four (4) centers are approved to participate (UW,
Duke, DFCI, OHSU)
– Most recent site approval 9/24/10
– One site was unable to bring up the trial due to late timing of
protocol approval
– Potential to accrue at least two (2) of the accrued 54 as they
may cross over to add on Dasatanib to ongoing Nilutamide
– One (1) patient out of the 12 did not receive both PET images
• Challenge: to reach 24 patient accrual goal – current
discussions to expand therapeutic study by 10 patients
Challenges
• Challenges
• Setting up IND tracer availability
• Companion Imaging on a subset of patients
• Delays to Site Readiness
• IRB approval for both the treatment and Imaging Trial slow
• Two (2) centers had IRB approval of the treatment trial before the
imaging trial and both accrued to treatment trial rapidly
• Radiology Interest
• Barriers to Accrual
• Inclusion/Exclusion to original Febbo trial
– (protocol was amended)
• Unable to accrue beginning patients as treatment trial was opened
prior to imaging trial
• Prostate cancer patients are elderly and many have painful bone
metastases - reluctance to lay in scanner for extended time
Plans For Next Year - 2011
• Completion of Accrual – Target by end of 2010
although treatment study may expand
• Complete PET Imaging and Data Collection for
6687 Patients
• Finalize Data Sharing with the Febbo Trial
• Continue Kinetic Analysis of PET Images
• Central Review of PET and Bone Scan Images
Thank You