ACRIN 6688
PHASE II STUDY OF 3'-DEOXY-3'-18F
FLUOROTHYMIDINE (FLT) IN INVASIVE
BREAST CANCER
Principal Investigator: Lale Kostakoglu, MD
9/30/10
[F-18] FLT Background
 Recent advances in cancer treatment occurred in
the development of disease specific molecular
agents, many of which induce cell cycle arrest
(cytostatic effect) inhibiting cell proliferation and
tumor growth
Evaluating alterations in DNA metabolism may
reflect therapy response better than changes in
glucose utilization
FDG reflects tm proliferation only in part and
associated with FPs due to tracer retention in
inflammatory processes
[F-18] FLT Background
 FLT is a structural analog of
thymidine
Although FLT is not incorporated
into DNA, it is trapped in the cell
due to phosphorylation by TK
FLT PET enables non-invasive
imaging and quantification of the
tm proliferative fraction in
proportion to DNA synthesis rate
FLT PET can be used as an
imaging probe to assess in vivo
cellular proliferation in malignant
tumors, especially with targeted
drugs
Buck AK, Methods 2009: 48:205
[F-18] FLT Background
 Because of lower overall tm uptake and high bckg
activity in the liver and bone marrow, FLT is not expected
to have the same sensitivity as FDG for tumor detection
across all organs
 FLT-PET is considered a potentially powerful tool to
 provide additional diagnostic specificity for proliferating tissues
 Provide important biological info that could have implications in
treatment selection or monitoring
Salskov A , Semin Nucl Med 2007;37:429
Preliminary Studies
proliferation dependent accumulation of FLT
Buck AK, Methods 2009: 48:205
The high cc’s observed between FLT uptake and Ki67 measurements implicate that
cellular uptake of FLT is predominantly caused by proliferative activity
Non-invasive detection and grading of malignant lymphoma
using FLT PET as surrogate marker of tumor proliferation
aggressive
lymphoma
Low grade
lymphoma
Ki-67
labeling
index:
>90%
Ki-67
labeling
index: < 5%
Buck AK, Methods 2009: 48:205
Kenny, EJNM 34:1339, 2007 FLT in BREAST CANCER
Aim: a. determine FLT-PET response at 1 wk in pts treated
with chemo b.determine the reproducibility of serial scans
•17 discrete lesions in 13 stage II–IV breast ca pts
•Imaging prior to and at 1 wk after treatment with chemo
•Clinical response assessed 60 dys after commencing chemo
•6 pts had a significant clinical response at day 60; these pts also had a
significant reduction in FLT uptake at 1 wk
•Decrease in SUV at 1 wk discriminated btw clinical response and SD
(p=0.02)
•FLT response generally preceded tm size changes
SUVmax in CR/PR
SUVmax in SD
Pre Therapy
7 dys posttherapy
7 dys posttherapy
Post Therapy
RESPONSE in a patient
with grade II lobular ca
NO RESPONSE in a
patient with grade II IDC
Kenny, EJNMMI 34:1339, 2007
Reproducibility of [18F]FLT Parameters
Kenny, EJNMMI 34:1339, 2007
Shields, AF, Clin Cancer Res. 2008;14:4463
The box plot shows the mean percent error (horizontal line within the box),
the 25th and 75th percentiles (bottom and top of box, respectively), and the
range (bottom and top horizontal bars on vertical whiskers).
VIRGINIA COMMONWEALTH UNIVERSITY
AMERICAN COLLEGE OF RADIOLOGY IMAGING NETWORK
ACRIN 6688
(amendment 6)
PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE
BREAST CANCER
Protocol Investigators
VCU Study Chair
Paul R Jolles, MD
Dept Radiology
Richmond, VA
prjolles@vcu.edu
vcu.edu
VCU Study Co-Chair
Harry D Bear, MD, PhD
Dept of Surgery
Richmond, VA
hdbear@vcu.edu
ACRIN Study Co-Chair
David Mankoff, MD, PhD
Professor of Radiology
Seattle Cancer Care Alliance
Seattle, WA
dam@u.washington.edu
VCU Study Statistician
Donna K McClish, PhD
Department of Biostatistics
Richmond, VA 23298
mcclish@mail2.vcu.edu
VCU Study Co-Chair
Michael O Idowu, MD
Dept of Pathology
Richmond, VA
midowu@mcvh-
ACRIN Study Co-Chair
Lale Kostakoglu, MD, MPH
Professor of Radiology
Mount Sinai School of Medicine
New York, NY 10029
lale.kostakoglu@mssm.edu
ACRIN Study Statistician
Fenghai Duan, PhD
Ctr for Statistical Sciences
Brown University
fduan@stat.brown.edu
Study Objective
Primary Objective:
To correlate the percentage change in SUVs
between baseline (FLT-1) and early-therapy
(FLT-2) with pCR (as a dichotoumous
variable) to neoadjuvant chemotherapy of
the primary tumor in patients with locally
advanced breast cancer (LABC)
Changed to early therapy from mid-therapy
Secondary Objectives
evaluate correlation or relationship between,
• FLT1 and FLT3 uptake parameters and proliferation markers
• FLT1, FLT2 and FLT3 uptake parameters and PCR of the primary tm and
residual cancer burden (RCB)
• FLT1, FLT2 and FLT3 uptake parameters and non-response of the primary
tm (SD or prog)
• FLT1, FLT2 and FLT3 uptake parameters and PCR to neoadjuvant in pts
with regional disease in the LNs
compare changes of,
• FLT2 and FLT3 uptake parameters to changes in tm sizes from other serial
imaging modalities (mammogram, MRI, and US, as available)
• FLT2 and FLT3 uptake parameters to metabolic changes from FDG PET,
as available
• monitor for potential safety issues and define any
physiologic effects associated with FLT administration
[F-18] FLT Study Outline
Establish Eligibility
Obtain pre-treatment
proliferative Indices
Baseline Imaging
• Baseline organ function
• Pathologically confirmed disease
• Determine primary systemic Rx
Ki-67 and mitotic index on bx sample
or re-biopsy (if available)
18FLT
PET/CT
(FLT-1)
18FLT
PET/CT
(FLT-2)
18FLT
PET/CT
(FLT-3)
Chemotherapy cycle 1
Early therapy Imaging
Chemotherapy last cycle
Post-therapy Imaging
Surgical Resection
Obtain post-treatment
proliferative Indices
• Pathologic response,
• Ki-67 and mitotic index,
surgical specimens
Timing of FLT PET Studies
 Three imaging sessions
• pre-treatment (FLT-1),
• after one cycle (FLT-2),
• at completion (FLT-3)
 FLT-1 (baseline PET) must be completed within 4 wks
prior to chemo initiation
 FLT-2 (early PET) must be performed 5-10 dys after
initiation of the first chemo cycle
 FLT-3 (post therapy PET) will be performed after the
completion of chemo and within 3 wks prior to surgery
Neoadjuvant Therapy
 There is no specific neoadjuvant chemo regimen
required for this protocol
 Several neoadjuvant therapy protocols are currently
used at participating institutions and subjects for the
study may be recruited from prospective
neoadjuvant chemo trials, which may also include
targeted agents, such as trastuzumab
 However, patients on neoadjuvant protocols using
hormonal therapy alone are not eligible
Inclusion Criteria
 Pathologically confirmed breast cancer, determined to be a candidate for
neoadjuvant therapy and for surgical resection of residual primary tm
after neoadjuvant therapy
 Tumor size >2cm, measured on imaging or estimated by PE
 No obvious contraindications for primary chemotherapy
 Residual tumor planned to be removed surgically following completion
of neoadjuvant therapy
 Age >18
 ECOG Performance Status ≤ 2 (Karnofsky ≥ 60%)
 Normal organ and marrow function at 1st visit:
-leukocytes ≥ 3,000/μl;
-absolute neutrophil count ≥ 1,500/μl;
-platelets ≥ 100,000/μl;
-total bilirubin within N institutional limits;
-AST(SGOT)/ALT(SGPT) ≤2.5 times institutional upper limit of N
-creatinine within normal institutional limits; OR creatinine
clearance ≥30 mL/min/1.73 m2 for pts with cr levels above normal;
Inclusion Criteria
 If female, postmenopausal for a min of one year,
OR surgically sterile, OR not pregnant, confirmed
by ß-HCG blood test, and willing to use adequate
contraception
 Able to understand and willing to sign a written
informed consent document and a HIPAA
authorization in accordance with institutional
guidelines
Exclusion Criteria





Prior treatment (any) to the involved breast
Uncontrolled intercurrent illness
Medically unstable
Unable to lie still for 1.5 hrs, requirement of anesthesia
History of allergic reactions attributed to compounds of
similar chemical or biologic composition to FLT
 Pregnant or nursing or age<18
 Previous malignancy, other than basal cell or squamous
cell carcinoma of the skin or in situ ca of the cervix, from
which the patient has been disease free for < 5 years
 Currently on hormone therapy as a primary therapy
(aside from hormonal replacement therapy)
Study Calendar
FLT PET/CT
Informed
Consent
Demographics
Medical History
Height
Weight
PE
CBC w/diff, Plts
Serum Chemistry
AE Evaluation
<4 wks
PreStudy
Pretherapy
Imaging
(FLT-1)
X
After 1 wk
(5-10 dys)
(FLT-2)
X
Posttherapy
Imaging
(FLT-3)
X
X
X
X
X
X
X
X
X
Surger
y
X
X
X
X
X
X
X
X
X
Study Procedures
Visit 1: Screening visit
-screening assessment will occur to determine eligibility
-signed consent form will be obtained prior to study trial
-CBC with differential and serum chemistry, and platelets.
-If data available from clinical records in the appropriate time window,
they need not be repeated for pre-study evaluation.
-medical history, demographics, height, weight, and PE
-tissue samples/slides from bx will be sent to VCU Pathology
Visit 2: FLT PET Imaging Studies (FLT1)
-baseline FLT PET scan; within 4 wks prior to chemo
Visit 3: FLT PET Imaging Studies (FLT2)
-early therapy FLT PET;5-10 dys after the initiation of 1st cycle
Visit 4: FLT PET Imaging Studies (FLT-3)
post therapy FLT PET;after chemo & within 3wks prior to surgery
Visit 5: Surgery
-After neoadjuvant chemo, surgical resection of residual tm
-A portion of residual tm sample/slides will be sent for to VCU Core Pathology for pathologic
analysis and proliferation assays within 2 wks post surgery
- If no viable tumor remains, a pCR will be documented
Imaging Sessions
 The participant will undergo [18F]FLT injection,
• immediately after injection a dynamic regional PET/CT imaging will
be done for 60 minutes
• dynamic imaging will be followed by a static whole body image from
top of head to upper thigh; 5-7 bed positions
• The preferred imaging sequence for the is to obtain the dynamic
PET imaging first, then followed by the torso survey using static
PET imaging, however, for patients who are unable to tolerate lying
in the scanner for dynamic imaging or for centers where scanner
availability/scheduling is limited, the acquisition of the SUV using
static PET imaging starting 60 minutes after injection fulfills the
needs of the study.
 Analyses
SUV30
SUV30-60
SUV60
Patlak slope
FluxFLT
k3
Data Analysis
FLT Parameters
Pre-Rx (FLT1) parameters
Compared To
Ki-67/mit index, biopsy
Clinical Response
Path. Response (pCR and RCB)
After one cycle (FL2) parameters
(absolute values and % change from FLT1)
Clinical Response
Response from other imaging
modalities (as available)
Path Response (pCR and RCB)
Post-therapy (FLT3) parameters
(absolute values and % change from FLT1)
Ki-67/mit index, surg spec
Clinical Response
Response from other imaging
modalities (as available)
Path. Response (pCR and RCB)
Pathologic Complete Response
 pCR is defined as the absence of viable invasive tumor at
histopathologic examination of the post-therapy surgical
specimen
 This analysis will be performed at the local treating site and
reviewed at the central site at VCU
 Presence of residual non-invasive cancer (DCIS) in the
absence of viable invasive cancer is still considered a pCR
 Dichotomous response assessment; pCR vs other than
pCR

A secondary related measure will also be assessed, the
residual cancer burden (RCB) which will be used for
secondary objectives (described in the protocol)
Clinical Response

Clinical Response as per routine by the treating physician
based upon the % change in anatomic tm size between the
pre, early-, and post-treatment time points

The assessment of size will be made per routine of the
treating physician and will typically be performed by one of
the following: PE, mammography, US, or breast MRI

The same method should be used consistently for each
patient throughout this study. The categorization of clinical
response is categorized as described in Table
Response Category
Complete Response (CR):
Criteria
Disappearance of the primary tumor
Partial Response (PR):
At least a 30% decrease in the LD of primary tm, from baseline LD
Progressive Disease (PD):
At least a 20% increase in the LD of primary tm, taking as
reference the smallest LD since treatment started
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor ncrease to qualify
for PD
Accrual Plot and Current Accrual Rate
Number of Sites Open
for Enrollment
Number of Sites
Accruing Patients
12
10
Study Accrual during
Year
Total Number
8
6
Last three months: 4
Average
2 pts/month
Last 3 months:
Avg 2 pts/month
2
0
Nov.
2009
Jan.
2010
Feb.
2010
Mar.
2010
Apr.
2010
May.
2010
Jun.
2010
Jul.
2010
Aug.
2010
Sep.
2010
Total
Number of Sites Open for Enrollment
1
1
1
2
3
4
4
7
9
12
12
Number of Sites Accruing Patients
1
1
1
1
1
1
1
3
5
5
5
Study Accrual during Year
1
1
0
2
0
0
0
3
3
0
10
Participating Institutions and Accrual Status
Opened
Accrual
University of Pennsylvania School of Medicine
3/4/2010
1
Washington University Medical School
7/28/2010
0
Thomas Jefferson University Hospital
5/4/2010
2
University of Washington
8/18/2010
0
Virginia Commonwealth University Health System
9/14/2009
7
Scottsdale Medical Imaging, LTD
7/28/2010
0
Milton S. Hershey Medical Center
9/21/2010
0
Excel Diagnostics Imaging Clinics
7/28/2010
1
Mount Sinai Medical Center
4/27/2010
1
Fox Chase Cancer Center
8/23/2010
0
University of Arkansas
9/24/2010
0
Wake Forest University
9/24/2010
0
THANK
YOU!