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

638s Sarcoma
10032^ Poster Discussion Session (Board #24), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I trial of panobinostat (P) and imatinib (IM) in patients with
treatment-refractory gastrointestinal stromal tumors (GIST). Presenting
Author: Sebastian Bauer, Sarcoma Center, West German Cancer Center,
Essen, Germany
Background: Panobinostat (LBH589; P) is a pan-deacetylase-inhibitor that
has preclinical activity in combination with IM in GIST models in vitro and
in vivo. Aim of this study was to determine the maximum tolerated dose
(MTD) and dose-limiting toxicities (DLT) of escalating doses of P in
combination with IM in patients with GIST who have failed IM and sunitinib
treatment. Methods: This was a two-center phase I study using a 3�3
design with a prespecified expansion of the MTD cohort. IM was administered
at a dose of 400mg qd. Following a 7 day run-in phase, escalating
doses of P were added. The starting dose for P was 20 mg given as a
three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Doses
were increased by 10 mg if no dose limiting toxicities emerged. Blood
samples were drawn for PK and biomarker assessments of IM, its main
metabolite N-desmethyl-IM, and P using a validated RP-HPLC method.
Acetylation of histone A3 was evaluated in peripheral blood mononuclear
cells (PBMNC) as pharmacodynamic marker for P activity. Metabolic
response using PET (EORTC-PET study criteria) was assessed on day 7 of
IM run-in and after 3 weeks of combined treatment with IM and P. Results:
In total 12 extensively pretreated (median 5 pretreatments) pts (4 f, 8 m;
median age 56 y, 34-75 y) received study treatment at 2 dose levels (DL). 2
dose-limiting toxicities (grade 4 thrombocytopenia) occurred at DL 2 (30
mg). Most common AEs were thrombocytopenia, anemia, fatigue, nausea,
emesis, diarrhea, creatinine elevation, abdominal cramping, and weight
loss. DL 1 (20mg) was declared MTD, and 5 additional pts were enrolled at
DL1. Analysis of P and IM PK revealed mean peak concentration of 14.8
�/- 9.5 ng/ml for P (20 mg). IM plasma concentrations with 400 mg
once-daily administration were 2.8 � 1.1 �g/mL at peak and 1.2 � 0.4
�g/mL at trough. Histone A3 acetylation was demonstrated in PBMNC from
pts treated at DL 1. 11 pts were evaluable for PET response: 1 had mPR, 7
had mSD and 3 had mPD. Longest treatment duration was 17 weeks
(median: 6wks). Conclusions: P in combination with IM is moderately
tolerated. Evidence of target inhibition at the MTD was associated with
limited clinical activity in heavily pretreated pts with GIST.
10034 General Poster Session (Board #46C), Sun, 8:00 AM-12:00 PM
Characteristics of sarcoma patients with long-term response to gemcitabine
and paclitaxel. Presenting Author: Daniela Katz, Sharette Institute of
Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Background: The combination of fixed-dose-rate gemcitabine and docetaxel
has demonstrated efficacy in advanced uterine leiomyosarcoma and nonleiomyosarcoma
sarcomas. We evaluated the tolerability and efficacy of
modified taxol-gemcitabine (GemTax) protocol for patient with advanced
sarcoma. The protocol was designed on a weekly basis to reduce toxicity.
The purpose of this retrospective study was to evaluate the characteristics
of long term-responders (�12 treatments) to weekly GemTax, among
pre-treated advanced high-grade sarcoma patients. Methods: From May
2004 to October 2011, 48 advanced sarcoma patients were treated with
combination paclitaxel (60-90 mg/m2) and gemcitabine (600-900 mg/m2
over 100 min), on days 1,8 of every 3-week cycle or on days 1, 8 and 15 of
every 4-week cycle at a wide-range treatment lines. Two patients are still on
the protocol. Results: Fifteen patients (6 males and 9 females) completed
12 weekly treatments or more (mean 22.3 range 12-37) of which 4
completed �30 treatments. These include 5 leiomyosarcomas (one retroperitoneal),
2 uterine leiomyosarcomas, 3 MFH, 2 spindle sarcoma, 1
osteosarcoma, 1 adamantimoma and 1 pleomorphic rhabdomyosarcoma.
GemTax was administered as 1st or 2nd line treatment in 2 and 8 patients,
respectively, and as 3rd -6th line in 5. Of these patients, none achieved
complete response (CR), 7/15 (47%) achieved a partial response (PR) and
8/15 (53%) had stable disease (SD). Median treatment duration was 10.3
months (range 4-22) Median progression-free survival was 28.85 months
(range 5-84 months), and median overall survival was 51.2 months (range
16-95 months). A lower starting dose of paclitaxel (60-70 mg/m2) and
gemcitabine (600-700 mg/m2) characterized the 4 patients with responses
�30 cycles. Only five patients required dose reduction ranging
between 10-40% due to grade 3 hematological toxicity. None of these
patients, however, had febrile neutropenia, or bleeding events, and all
non-hematologic toxicities including neurotoxicity were manageable.
Conclusions: GemTax is a reasonable treatment option for patients with
advanced pre-treated high-grade sarcomas. The regimen is well tolerated
and dose adjustments do not seem to impact response.
10033 Poster Discussion Session (Board #25), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Dasatinib first-line treatment in gastrointestinal stromal tumors: A multicenter
phase II trial of the SAKK (SAKK 56/07). Presenting Author:
Michael Montemurro, Centre Pluridisciplinaire d’Oncologie, University
Hospital Lausanne, Lausanne, Switzerland
Background: First line imatinib has improved the outcome of patients (pts)
with gastrointestinal stromal tumor (GIST), but primary and secondary
resistance remain a problem. Dasatinib is a second generation tyrosine
kinase inhibitor (TKI) and inhibits the activity of bcr-abl, src-family kinases
along with a number of other oncogenic kinases including kit. In vitro,
dasatinib has shown activity against imatinib-resistant cell lines. Routinely,
pts diagnosed with GIST and treated with TKIs are monitored by
computed tomography (CT). 18F-fluorodeoxyglucose positron-emissiontomography
(FDG-PET) measures tumor metabolic activity for early response
assessment, which might be of particular use in the clinical trial
setting. Methods: This two-stage phase II trial investigated dasatinib in pts
with TKI-naïve GIST. Dasatinib starting dose was 2x70mg/day in pts with
histologically proven, FDG-PET positive GIST. Response evaluation was
done by serial CT and FDG-PET using EORTC PET response criteria (Young
et al. 1999). Elective surgery was allowed after 6 months of trial treatment.
Primary endpoint was response (CR�PR) by FDG-PET after one month of
dasatinib. Results: 47 of planned 52 pts have been enrolled from December
2007 to November 2011, when the trial was terminated due to slow
accrual. 43 pts were eligible. Median age was 61 years, 24 pts were male,
19 female and 41 had a performance status of 0 or 1. At a median
follow-up of 11.9 months, 20 pts were still on treatment. Pts went off trial
for elective surgery (n�6), progression (n�11), toxicity (n�3), and three
patients died (one on-drug). 5% of pts experienced G4, and 38% of pts G3
toxicity, which were most often gastrointestinal or pulmonary. 28% had
their dose reduced or interrupted. The primary endpoint, FDG-PET response
rate (CR�PR) at 4 weeks was 67% (13 CR, 16 PR, 7 SD, 3 PD, 4
not evaluable). Median progression-free survival is 11.1 months and
median overall survival not yet reached. Conclusions: Dasatinib shows
promising efficacy in TKI-naïve pts with FDG-PET positive GIST. Mutational
data will be presented at the meeting.
10035 General Poster Session (Board #46D), Sun, 8:00 AM-12:00 PM
Effect of metastasis surgery on overall survival in patients (pts) with
advanced soft tissue sarcoma (ASTS): A subanalysis of the PALSAR trials.
Presenting Author: Nuria Kotecki, Centre Oscar Lambret, Lille, France
Background: The role of surgery in pts with ASTS remains controversial. We
have conducted an exploratory retrospective analysis of the role of metastasis
surgery in ASTS pts receiving 1st-line chemotherapy (CT). Methods: The
database includes all pts enrolled in PALSAR-1 and PALSAR-2 trials
[Fayette 2009; Bui-Nguyen 2011], treated with dose-intensified MAID or
high-dose CT with peripheral blood stem cells support as 1st-line treatment
of ASTS. In our analysis, the primary endpoint is overall survival (OS).
Log-ranks are used for univariate analysis and Cox model for multivariate
analysis. Impact of treatments had been evaluated after adjustment to
confounders (Cox Model). Confounders were defined as parameters with
significantly different distribution in pts who underwent metastasis surgery
and those who did not (p�0.05) and significantly associated with OS
(p�0.05). Results: The database consists of 410 pts (160 in PALSAR-1
and 248 in PALSAR-2) with a median age of 43. Among them, 77 patients
(18%) underwent metastasis surgery. At the end of the treatment, 61 pts
experienced complete response (CR), 45 with CT alone and 16 with
metastasis surgery and CT. The median follow-up was 29 months. The
median OS was 35.7 months (29.9-41.5). The following parameters are
associated with longer OS in univariate analysis: primary location
(p�0.0001), performance status (p�0.010) and absence of liver metastasis
(p�0.001). We identified 4 factors associated with metastasis surgery
(n�76): limb/trunk primaries, young age, absence of liver metastasis and
absence of progression of the target lesions after 4 cycles. The sole
identified confounder was primary location. In multivariate analysis the 2
categories of patients experiencing significant longer OS are those with CR
without surgery (HR�2.2, [1.7-5.8], p�0.0001) and those with CR
following metastasis surgery (HR�3.8, [2.3-6.2], p�0.0001). Conclusions:
Among the pts with ASTS receiving poly-CT as 1st-line treatment, the OS of
pts experiencing CR with or without metastasis surgery appears similar.
Metastatis surgery without CR does not offer significant OS advantage.
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