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

10084 General Poster Session (Board #52E), Sun, 8:00 AM-12:00 PM
Activity of MK1775, a selective Wee1 inhibitor, alone or in combination
with gemcitabine, in sarcomas. Presenting Author: Jenny Kreahling, H. Lee
Moffitt Cancer Center & Research Institute, Tampa, FL
Background: Sarcomas consist of more than 50 subtypes of mesenchymal
tumors. Doxorubicin alone or in combination has been the primary therapy
for treatment of sarcomas; however, the response rates are suboptimal in
many of the more common adult subtypes of soft tissue sarcoma.
Accordingly, new agents are needed for the treatment of this heterogeneous
group of diseases. Wee1 is a critical component of the G2/M cell cycle
checkpoint control and mediates cell cycle arrest by regulating the
phosphorylation of CDC2. Methods: MK1775 treatment of multiple sarcoma
preclinical models at clinically relevant concentrations leads to
unscheduled entry into mitosis and initiation of apoptotic cell death. In our
current study we have investigated the therapeutic efficacy of MK1775 in
sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo in a
xenograft model of osteosarcoma both alone and in combination with
gemcitabine. Results: In patient-derived bone and soft tissue sarcoma
samples ex vivo treatments show MK1775 in combination with gemcitabine
causes significant apoptotic cell death suggesting that this treatment
may represent a novel approach in the treatment of sarcomas. The cytotoxic
effect of Wee1 inhibition on sarcoma cells appears to be independent of
p53 mutational status. Furthermore, in a patient-derived osteosarcoma
xenograft mouse model we show the therapeutic efficacy of MK1775 in vivo
by utilizing magnetic resonance imaging (MRI) and diffusion MRI methods.
Our data shows MK1775 in combination with gemcitabine dramatically
slows tumor growth, increases apoptotic cell death and increases CDC2
activity. Cell viability, a clinically established prognostic indicator of
survival, was lowest with the combination and very low in animals treated
with MK1775 alone. This was mainly due to increased mineralization of the
tumors. Caspase-3 was increased in MK1775 treated animals by immunohistochemistry
as well. Conclusions: These results together with the
promising safety profile of MK1775 strongly suggest that this drug can be
used as a potential therapeutic agent alone or in combination with
gemcitabine in the treatment of both adult as well as pediatric sarcoma
patients.
10086 General Poster Session (Board #52G), Sun, 8:00 AM-12:00 PM
Early assessment of MCV to predict clinical outcome in patients with
advanced gastrointestinal stromal tumors (GIST) receiving imatinib. Presenting
Author: Anastasia Constantinidou, The Royal Marsden Hospital NHS
Foundation Trust and the Institute of Cancer Research, London, United
Kingdom
Background: In patients with advanced GIST, imatinib trough levels have
been associated with a lower rate of clinical benefit. Anecdotal observations
have suggested that commencing treatment with imatinib may be associated
with an increase in red blood cell size as measured by MCV and MCH,
indicating the effect of imatinib on KIT signalling in the bone marrow.
Methods: In this retrospective review we examined a possible connection
between changes in MCV and MCH after the first 3 months (mo) of
treatment with imatinib and progression-free survival (PFS). Data for
patients with inoperable advanced or metastatic GIST treated between
2000 and 2011 were available for analysis. Patients were categorised in
quartiles according to the distribution of the percentage of change of MCV
and MCH between start of imatinib (baseline) and 3 (�/- 0.5) mo (ratio
%�MCV change at 3 mo/MCV at baseline). PFS curves were plotted using
the Kaplan-Meier method and compared using the log rank test. Results:
One hundred and thirty patients were eligible for analysis and the
demographics were: male:female 84:46, median age at presentation: 60.5
(23.5-86.5) years, commonest primary tumour sites: stomach (72/130)
and small bowel (44/130), commonest metastatic site: liver (76/130). In
the patients with a 10% or over increase in MCV (p75-p100) at the 3 mo
(�/-0.5) time point a significantly longer PFS was observed compared to
those with a smaller magnitude of change (PFS of 37.1 mo vs 24.3 mo,
p�0.032). A similar trend although not statistically significant was
observed in patients with MCH of 15% or over (p75-p100) with PFS of
34.0 mo vs 25.8 (p�0.125). The two parameters (MCV and MCH) showed
a high correlation of percentage change (r2�0.85). The patients with a
10% MCV increase and /or 15% MCH increase (total�40) showed a
significantly longer PFS (34.0 mo) compared to those with lower percentage
change (PFS� 24.3) p�0.035. Conclusions: Simple laboratory parameters
may be indicators of imatinib pharmacokinetics and may therefore be
used as surrogate markers of clinical outcome. Larger prospective studies
are required to confirm the results of this study.
Sarcoma
651s
10085 General Poster Session (Board #52F), Sun, 8:00 AM-12:00 PM
Pharmacokinetics of escalated dose of imatinib in patients with advanced
gastrointestinal stromal tumors. Presenting Author: Changhoon Yoo, Department
of Oncology, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, South Korea
Background: Although escalated dose (ED, 800 mg daily) of imatinib (IM) is
one of important options in resistant gastrointestinal stromal tumors (GIST)
on standard dose (SD, 400mg daily), there has been lack of pharmacokinetic
data at ED. We therefore explore the potential relationship between
IM plasma trough level (Cmin), and clinical outcomes or toxicities in
patients treated with ED. Methods: Between 2008 and 2011, steady-state
IM Cmin was measured in 66 patients with GIST who received ED of IM
using liquid chromatography-tandem mass spectrometry. Percent change
from IM Cmin at SD was calculated in 43 patients that both SD and ED IM
Cmin were measured. The association with efficacy and toxicity was
analyzed with grouping patients into quartiles according to IM Cmin at ED
and percent change. Results: Median age was 59 years (range, 36–77) and
40 patients were male. KIT exon 11 and 9 mutation was detected in 32 and
18 patients, respectively. At ED, partial response was achieved in 4
patients (6%) and stable disease was in 32 patients (48%). The median
progression-free survival was 4.2 months (95% CI, 1.8-6.6) and overall
survival was 38.5 months (95% CI, 7.6-69.3). The mean (� standard
deviation) IM Cmin at ED was 3552 (� 1540) ng/mL. IM Cmin was
significantly increased after dose escalation (p �0.001), and mean percent
change from IM Cmin at SD was 162% (� 100). Body surface area
(p�0.01), hemoglobin (p�0.001), and neutrophil count (p�0.006) were
significant covariates for IM Cmin at ED in multivariate analysis. The group
of quartiles of IM Cmin at ED and percent change was not associated with
response and survival outcomes. However, grade 3-4 hematologic or grade
2-4 non-hematologic toxicity was observed in 9% (1/11) of patients in the
lowest percent change quartile (Q1, �90%) compared with 56% (18/32)
in Q2 to Q4 (p�0.012), although absolute values were not associated with
toxicity. Conclusions: In GIST patients treated with ED of IM, IM Cmin was
not associated with response and survival. Clinically significant toxicity
following dose escalation was correlated with percent change of IM Cmin, rather than absolute values. Monitoring of IM Cmin might help to predict or
manage ED of IM induced toxicity.
10087 General Poster Session (Board #52H), Sun, 8:00 AM-12:00 PM
SDHA and SDHB mutations in KIT/PDGFRA WT gastrointestinal stromal
tumors. Presenting Author: Margherita Nannini, Seragnoli Department and
GIST Study Group, University of Bologna, Bologna, Italy
Background: KIT/PDGFRA wild-type (WT) GISTs harbour mutations on
SDHB and SDHC and, more recently, we described mutations on SDHA
using massively parallel sequencing approach. We sequenced SDHA and
SDHB genes in a larger series in order to validate the data. Methods: SDHA
gene (1-15 exons) and SDHB gene (1-8 exons) (even not all exons in all
samples) were sequenced on tumor (T) and/or peripheral blood (PB) of WT
GIST patients by Sanger Sequencing method. DNA was extracted from
tumor specimens by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) and
amplified with specific primer pairs designed to amplify exons but not
SDHA pseudo-genes located on chromosomes 3 and 5. Then, PCR products
were purified with the Qiaquick PCR purification kit (Qiagen, Milan, Italy)
and sequenced on both strands using the Big Dye Terminator v1.1 Cycle
Sequencing kit (Applied Biosystems). Sanger sequencing was performed
on ABI 3730 Genetic Analyzer (Applied Biosystems). Results: SDHA gene
exons were sequenced on a total of 27 WT GIST patients, in particular on T,
PB and both from 12, 6 and 9 patients respectively. SDHB gene exons were
sequenced on a total of 18 out of 27 patients, in particular on T, PB and
both from 7, 8 and 3 patients respectively. 8 SDHA mutations were found
in 5 samples (18.5%). Besides those previously identified, 5 new SDHA
mutations were found in other 3 samples: one sample harboured R171C
and R589Q heterozygous missense mutation in exons 5 and 13 respectively.
The other one harboured G419R and E564K heterozygous missense
mutations in exons 9 and 13 respectively. The third sample harboured a
delCAG immediately upstream of exon 5, in heterozygosis on PB and in
homozygosis on T. A SDHB heterozygous mutation (301delT) in exon 4 was
found on 1 PB sample. Conclusions: the presence of SDHA mutations has
been confirmed in a subgroup of WT GIST patients. All subunits of SDH
complex should be sequenced on WT GIST patients in order to explore the
frequency and any linkage between each other and the pathogenetic and
clinical significance.
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