Annual Meeting Proceedings Part 1 - American Society of Clinical ...

624s Pediatric Oncology
9573 General Poster Session (Board #43D), Sun, 8:00 AM-12:00 PM
Do children, adolescents, and young adults with soft tissue sarcoma benefit
from early detection of recurrences? Results of a population-based study.
Presenting Author: Tobias M. Dantonello, Olgahospital, Pediatrics 5,
Klinikum Stuttgart, Stuttgart, Germany
Background: Most patients with pediatric soft tissue sarcoma (PSTS)
achieve a 1st remission with primary therapy, but recurrences are frequent
and drive mortality. Relapse detection (RD) is the foundation of posttreatment
surveillance. The rationale for frequent follow-up investigations
is RD in an early stage with better salvage options. There is however little
evidence regarding the value of early asymptomatic RD and it was not
investigated by any larger or population-based study in PSTS. We determined
whether early radiographic RD in asymptomatic patients improves
post-relapse outcome. Methods: Patients aged � 18 years at first referencereviewed
PSTS-diagnosis registered with CWS were enrolled if a 1st relapse
occurred between 1/2003 and 7/2010. The methods of RD and their
impact on outcome were evaluated. The data were correlated with the
German Childhood Cancer Registry (GCCR), which receives all information
about cancer patients � 18 years. Results: 235 patients from Germany (n �
212) and Sweden/Switzerland (n � 23) were eligible. In 2010 all German
PSTS-patients were registered both with the GCCR and CWS. The most
common PSTS-histiotypes were embryonal (n � 76) and alveolar (n � 74)
rhabdomyosarcoma. 156 patients had primary nonmetastatic PSTS. The
median time to relapse diagnosis (TTRD) was 1.4 years. 118 recurrences
were locoregional, 38 combined and 79 metastatic. In 229 patients, the
methods leading to RD could be evaluated. 139 recurrences were detected
because of clinical signs and symptoms, primarily observed by patients
and/or parents in 72%. 90 RDs were radiographic in asymptomatic
patients. TTRD did not differ between symptomatic and asymptomatic
patients. As of 12/2011, 77/235 patients are currently alive with a median
follow-up of 5.4 years. Overall survival from primary surgery at 3-, 5-, and
10-years for all 235 patients was 49%, 34% and 22%. It was 43%, 29%
and 23% for the symptomatic and 59%, 40% and 21% for the asymptomatic
group (p � 0.05). Conclusions: In this series, early radiographic RD in
asymptomatic PSTS-patients had no significant impact on TTRD or
post-relapse survival, although asymptomatic patients tended to survive
longer.
9575 General Poster Session (Board #43F), Sun, 8:00 AM-12:00 PM
Use of pharmacokinetic modeling to optimize direct inhibition of the
�undruggable� target EWS-FLI1 of Ewing sarcoma. Presenting Author:
Jeffrey Toretsky, Georgetown Lombardi Comprehensive Cancer Center,
Washington, DC
Background: Chimeric transcription factors are ideal anti-cancer targets;
however, they lack enzymatic activity thus rendering them ‘undruggable’
proteins. The EWS-FLI1 fusion protein of Ewing sarcoma (ES) has been
validated as an anticancer target both alone and as a partner of RNA
Helicase A (RHA). Our prior work identified the small molecule YK-4-279
as a specific inhibitor that blocks RHA from binding to EWS-FLI1. Blocking
this interaction leads to apoptosis. We have modeled YK-4-279 treatment
using ES cells to establish the duration of YK-4-279 exposure that leads to
apoptosis. Methods: Apoptosis was measured by caspase-3 cleavage. A
validated plasma detection method allows for HPLC measurement of
YK-4-279. Pharmacokinetic (PK) models of YK-4-279 for both intraperitoneal
(IP) and intravenous (IV) administration were developed in SD rats and
BL6 mice. Results: ES cell lines were exposed to YK-4-279 over a
time-course, followed by a caspase-3 activity assay that demonstrated a
minimum of 16 hours exposure was necessary to achieve maximal
apoptosis using either 3 or 10 microM compound. A dose-dependency
assay demonstrated that while apoptosis could be achieved with 30 – 80
microM YK-4-279 after 4 hours of treatment, caspase-3 activity was less
than or equal to 3 microM for 16 hours. Rat PK modeling demonstrated a
t1/2 of 30 minutes following IV administration. BL6 mice demonstrated
similar kinetics to the rat. SCID/bg mice, which are necessary for tumor
efficacy studies, demonstrated approximately 50% faster clearance than
either rat or BL6 mice. Absolute bioavailability for IP administration was
41%. Conclusions: Models will be created to optimize IP dosing regimen.
The optimized IP dosage and dosing intervals will be evaluated in tumor
bearing animals in order to advance development of YK-4-279. The results
of these studies will be used to guide toxicology studies in animals. In
addition, pharmacodynamics models are being developed to compare
YK-4-279 levels with functional activity. The combined results of these
investigations will lead to human clinical trials for this first-in-chemical
class, first-in-mechanism drug candidate.
9574 General Poster Session (Board #43E), Sun, 8:00 AM-12:00 PM
A multidisciplinary treatment comprising standard chemotherapy with
vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide
for Ewing sarcoma family of tumor (ESFT) in Japan: Results of the first
Japan Ewing Sarcoma Study (JESS) 04. Presenting Author: Atsushi
Makimoto, National Cancer Center Hospital, Tokyo, Japan
Background: Survival rate of ESFT in Japan was reportedly less than 50% in
1990s. The JESS started in order to improve this condition by conducting
clinical trials for ESFT in Japan. Methods: This is a phase II, nonrandomized
trial to test safety and efficacy of multidisciplinary treatment
for non-metastatic ESFT. Age under 30 is eligible. Chemotherapy regimens
are alternating vincristine 1.5 mg/m2 on day 1, doxorubicin 37.5 mg/m2 on
days 1 and 2, cyclophosphamide 1200 mg/m2 on day 1 (VDC) and
ifosfamide 1800 mg/m2 on days 1 through 5 and etoposide 100 mg/m2 on
days 1 through 5 (IE) repeating every 21 days for 52 weeks. Local
treatment includes surgical resection and/or radiation therapy, of which
dosage varies from 0 to 55.8 Gy based on margin of the resection and
pathological response. Primary endpoint is 3 year progression free survival
(PFS). Statistical design was made to test whether the lower limit of 90%
confidence interval (CI) of PFS will exceed the threshold of 60%. Planned
sample size is 53 patients including 10% ineligible patients. Results:
Fifty-three patients were registered from December 2004 to May 2008.
Among the 53 patients, 7 patients were judged ineligible after the
registration (metastatic disease 1, changed diagnoses 6). Forty six patients
were considered as per protocol set and used for efficacy analyses. Three
year PFS is 71.7% (90% CI: 0.59 – 0.81). Estimated 5 year PFS and OS
are both 69.6%. Radiographic response rate (RR) in evaluable 38 patients
is 71.1% and pathological RR in 25 is 52.0%. In safety data, hematological
toxicities are significant such as grade 4 neutropenia observed in 98%.
Although there is no previously unknown adverse event reported, there are
three patients who experienced secondary malignancies (ALL 1, MDS 1,
osteosarcoma 1). Conclusions: A multi-disciplinary treatment comprising
standard multi-agent chemotherapy with vincristine, doxorubicin, cyclophosphamide,
ifosfamide and etoposide improved outcome of Ewing sarcoma
family of tumor in Japan although statistical confirmation of absolute
efficacy was not successful.
9576 General Poster Session (Board #43G), Sun, 8:00 AM-12:00 PM
Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in
children with high-risk neuroblastoma. Presenting Author: Ami V. Desai,
The Children’s Hospital of Philadelphia, Philadelphia, PA
Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb)
that significantly improves survival in high-risk neuroblastoma, was previously
reported to be highly variable in children, and its clearance (CL, 130
mL/h · m2 ) and volume of distribution (Vdss, 32 L/m2 ) were �10-fold
higher than the CL and Vdss of other cMoAbs. Characterizing the PK of
ch14.18 and the factors responsible for its variability could lead to
alternative dosing strategies that reduce toxicity. Methods: Detailed PK
sampling was performed prior to, during and for 25 d after 4 daily 10 h
infusions of 25 mg/m2 of ch14.18 administered with sargramostim
(ANBL0032) in children enrolled on an IRB-approved institutional correlative
protocol supported by United Therapeutics Corp. Ch14.18 concentrations
were measured with a validated ELISA with a lower limit of detection
of 0.44 mcg/mL. PK parameters were derived using non-compartmental
methods and reported as median (range). Results: 5 males and 4 females,
median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on
cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were
re-studied on C3. Data from 3 patients are not included because pretreatment
plasma samples contained a substance that interfered with the
ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and
ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220
(120-390) h, and the CL was 11 (3.8-16) mL/h · m2 , which is similar to
the average CL of 4 other cMoAbs (11 mL/h · m2 ). The Vdss of 2.8 (1.2-3.9)
L/m2 approximated blood volume and was similar to the Vdss of other
cMoAbs (1.7 L/m2 ) and humanized MoAbs (2.8 L/m2 ). AUC0-� in 2 patients
studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690
mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children
are similar to those in adults receiving ch14.18 at the same dose and
similar to other cMoAbs. Ch14.18 PK in children was less variable than
previously reported. The identity of the interfering substance in the plasma
of some patients requires further investigation. A limited sampling strategy
will be developed from these data for use in larger multi-institutional PK
studies of ch14.18.
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