Paper 020
PRELIMINARY ANALYSIS OF PHASE I, FIRST IN
HUMAN, CATHEPSIN ACTIVATED TUMOR IMAGING
PROBE
Brian E. Brigman, MD, PhD1; Melodi Javid2;
Diana Cardona3; Joan Cahill4; Jeffrey Mito2;
Jorge Ferrer5; Erin O'Reilly6; William C. Eward1;
Daniel Blazer7; Kyle Cuneo9; Ivan Spasojevic8;
David G. Kirsch4
1Orthopaedic Surgery, Duke University, Durham, NC,
USA; 2Pharmacology and Cancer Biology, Duke
In vivo treatment of STS bearing NOD/SCID mice with i)drug vehicle only,ii)
trabectedin once a week e.v. for 4 weeks, iii) olaparib i.p. for 5 days a week for
4 weeks , iv) the combination of the two. significantly reduced tumor gowth of
s.c. xenograts (A), and experimental metastasis in lungs (B).
University, Durham, NC, USA; 3Pathoogy, Duke
University, Durham, NC, USA; 4Radiation Oncology,
Duke University, Durham, NC, USA; 5Lumicell
Diagnostics, Waltham, MA, USA; 6Translational Medical
Institute, Duke University, Durham, NC, USA; 7General
Surgery, Duke University, Durham, NC, USA; 8Medicine,
Duke University, Durham, NC, USA; 9Radiation
Oncology, University of Michigan, Ann Arbor, MI, USA
Objective: The goal of surgical management of sarcoma
is complete resection of the tumor. The completeness of
resection is difficult to assess, particularly intra-operatively.
An intra-operative, cathepsin-activated fluorescent
probe and imaging camera is able to predict local recurrence
in a genetically engineered mouse model of soft
tissue sarcoma. This system is able to image soft tissue
sarcoma in de novo canine tumors as well. Here we
present preliminary phase I, first-in-human, results of the
use of the probe (LUM015) in human sarcoma patients.
The purpose of the study is to determine a safe dose of
LUM015 that effectively labels tumors.
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Methods: Methods: An IRB approved phase I, open-label,
single center, nonrandomized trial comparing up to
four dose cohorts employs a modified 3+3 design, with
dose cohorts: -1 to 3 (0.25, 0.5, 1 and 1.5 mg/kg). At the
highest dose that does not cause a clinically meaningful
side effect in the 3 patient cohort, an additional 3
patients will be enrolled. Inclusion criteria include sarcoma
patients greater than 18 years old with at least 1
cm of tumor undergoing resection surgery. The Safety
Monitoring Committee meets after each dose cohort
is full or if a clinically meaningful side effect is noted.
Patients are admitted to the research unit the day prior to
surgery and monitored overnight after administration of
the probe through a slow IV push. The patient undergoes
standard resection surgery ~24h after probe administration.
In the pathology suite, the tumor and samples of
surrounding margin are imaged with the imaging camera.
Specimens from imaged areas are harvested for histological
evaluation and cathepsin measurement.
Results: Results: At the time of abstract submission, 5
patients had been enrolled (cohorts 1 and 2). No clinically
meaningful side effects were noted. Analysis of the
LUM015 concentration-time curve for dose 1 cohort (0.5
mg/kg) gave a maximum serum concentration (Cmax) =
14.5±1.5 μg/mL, area under curve (AUC) = 79.8±8.7 hr
μg/mL. The curve had a triphasic appearance with a serum
half life of 3-4 h. We have been able to differentially label
tumor and normal tissue.
Conclusion: Conclusion: Preliminary results of LUM015
in human patients indicate that the drug is safe and well
tolerated at the dosages that have been given and that we
can differentially label tumor and normal tissue. Additional
patients will be enrolled at higher dosing cohorts to better
evaluate safety, pK and labeling efficacy.
Fluorescent imaging (top) and correlative histology (bottom)
from multiple areas of a single case of undifferentiated
pleomorphic sarcoma in a human patient.
Paper 021
INFILTRATIVE SOFT TISSUE SARCOMA SHOULD WE EXCISE BEYOND RADIOLOGICAL
INFILTRATION?
Shintaro Iwata, MD1; Tsukasa Yonemoto1;
Akinobu Araki2; Dai Ikebe2; Hiroto Kamoda1;
Yoko Hagiwara1; Takeshi Ishii1
1Div.Orthopaedic Surgery, Chiba Cancer Center, Chiba,
Japan; 2Div.Surgical Pathology, Chiba Cancer Center,
Chiba, Japan
Objective: Tumor infiltration, frequently observed in spindle
cell sarcomas of soft tissue, is often associated with an
inadequate surgical margin and results in failure of local
control. The purpose of this study is to determine whether
radiological tumor infiltration in spindle cell sarcomas
correlates with histological infiltration and whether tumor
resections with infiltration-free margins improve their local
control.
Methods: We retrospectively reviewed 41 patients diagnosed
with myxofibrosarcoma, undifferentiated pleomorphic
sarcoma, and leiomyosarcoma who underwent
initial surgery at our institute between 2007 and 2011 .
Radiological infiltration (R-inf) was measured by the length
of high-intensity tail-like extension as observed in either
STIR or gadolinium-enhanced fat-suppressed (GdFS) MRI.
Histological infiltration (H-inf) was defined as the distance
from the tumor edge to the end of the atypical tumor cells
on the histological mapping described by musculoskeletal
tumor pathologists (Fig.1). Correlation between R-inf and
H-inf was analyzed using the Pearson's correlation coefficient.
Local control rate (LCR) and overall survival (OAS)
were analyzed using the Kaplan-Meier method, and the
association of potential prognostic factors with LCR and
OAS were analyzed using the log-rank test and the Cox
proportional hazards regression model.
Results: Four patients (9.8%) out of 41 showed local
failure. Five-year OAS and LCR were 81.5% and 89.4%,
respectively. R-inf (range, 0-67mm) and H-inf (rang, 060mm) were observed positive in 19 (46%) and 20 (49%)
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patients, respectively. R-inf obtained by GdFS MRI images
(R2=.59) showed a stronger correlation to the H-inf than
that obtained by STIR image (R2=.28) (Fig.2). Univariate
analysis with 5-year LCR demonstrated that a positive
margin with not only tumor mass but also infiltrative tumor
cells was a significant prognostic factor compared with a
wide margin (p=.0017). Positive R-inf (p=.0047) and Hinf
(p=.047) were also significant factors predicting local
failure. In the multivariate analysis, wide resection with an
infiltration-free margin remained a significant factor predicting
favorable local control.
Fig.1 Radiological infiltration (R-inf) and Histological
infiltration (H-inf).
Fig.2 Scatter plot showing H-inf versus R-inf.
Conclusion: Radiological infiltration of spindle cell sarcoma
as assessed by GdFS MRI images correlated with
histological infiltration. In addition, our results suggest
that wide resection with an infiltration-free margin would
improve local control of these sarcomas.