Et 743 1606

A retrospective analysis of antitumour activity with trabectedin
in translocation-related sarcomas
Axel Le Cesne
a,
, Sara Cresta
b
, Robert G. Maki
c
, Jean Yves Blay
d
, Jaap Verweij
e
,
Andres Poveda
f
, Paolo G. Casali
g
, Carme Balan a
h
, Patrick Scho ski
i
, Federica Grosso
j
,
Pilar Lardelli
k
, Antonio Nieto
k
, Vicente Alfaro
k
, George D. Demetri
l
a
Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France
b
Department of Oncology, Fondazione Istituto Nazionale dei Tumori, Milano, Italy
c
Mount Sinai Medical Center, New York, NY 10029, United States
d
Department of Medical Oncology, Centre Le on Be rard, Lyon, France
e
Department of Medical Oncology, Erasmus University Medical Centre-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
f
Department of Medical Oncology, Instituto Valenciano de Oncologa, Valencia, Spain
g
Department of Cancer Medicine, Instituto Nazionale Tumori Oncology, Oncology, Milano, Italy
h
Medical Oncology Service, Institut Catala dOncologia Germans Trias I Pujol, Badalona/Barcelona, Spain
i
Department of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
j
Department of Oncology, SS Antonio & Biagio & C Arrigo General Hospital, Alessandria, Italy
k
PharmaMar, Clinical R&D, Colmenar Viejo Madrid, Spain
l
Center for Sarcoma and Bone Oncology and Ludwig Center, Dana-Farber Cancer Institute and Harvard Medical School, Oncology, Boston, MA,
United States
KEYWORDS
Antitumour activity
Chimeric fusion onco-
proteins
Chromosomal transloca-
tion
Sarcoma
Trabectedin
Abstract Aims: Approximately 20% of soft tissue sarcomas (STS) have subtype-specic
chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal
transcription factors. Since trabectedin can bind to DNA and displace transcription factors,
antitumour activity was explored in translocation-related sarcoma (TRS) subtypes.
Methods: The current retrospective pooled analysis includes data from 81 patients with TRS
treated in 8 phase II trials.
Results: TRS subtypes were: synovial sarcoma (SS, n = 45), myxoid-round cell liposarcoma
(MRC-L-sarcoma, n = 27), alveolar soft part sarcoma (ASPS, n = 4), endometrial stromal
sarcoma (ESS, n = 3) and clear cell sarcoma (CCS, n = 2). All but one patient had received
prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles
(range, 148; median dose intensity = 0.40 mg/m
2
/week). Partial responses according to
Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients
0959-8049/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejca.2012.05.012
Corresponding author: Address: Institut Gustave Roussy, Depart ment of Medical Oncology, 39 rue Camille Desmoulins, 94805 Villejuif Cedex,
France. Tel.: +33 1 42 11 43 16; fax: +33 1 42 11 52 19.
E-mail address: lecesne@igr.fr (A.L. Cesne).
European Journal of Cancer (2012) xxx, xxxxxx
Avai l abl e at www. s ci encedi r ect . com
j our nal homepage: www. ej conl i ne. com
Please cite this article in press as: Cesne A.L. et al., A retrospective analysis of antitumour activity with trabectedin in translocation-related sar-
comas, Eur J Cancer (2012), http://dx.doi.org/10.1016/j.ejca.2012.05.012
(ORR = 10%; 95% CI, 419%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour
control rate (ORR plus stable disease) was 59% (95% CI, 4870%). Median PFS was
4.1 months (6-month PFS rate = 40%). Median overall survival was 17.4 months (survival
rate at 12 months = 60%). Trabectedin had a manageable safety prole.
Conclusion: Trabectedin demonstrates encouraging disease control in TRS. Since these prom-
ising results were generally noted in patients following chemotherapy, a phase III randomised
trial in rst-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in
patients with TRS.
2012 Elsevier Ltd. All rights reserved.
1. Introduction
Chromosomal translocations are the most frequent
molecular alterations in sarcomas, and occur in around
20% of cases.
14
Sarcoma translocations and the associ-
ated chimeric oncoproteins that they generate provide
attractive targets for therapeutic intervention given that
these fusion proteins are critical for disease pathogenesis
and tumour cell survival, and no alternative pathways
exist to avoid their blockade.
58
Trabectedin is a marine-derived antineoplastic agent,
initially isolated fromthe tunicate Ecteinascidia turbinata
and currently produced synthetically, which has shown
antitumour activity in advanced soft tissue sarcoma
(STS),
911
as well as in other malignancies such as
relapsed ovarian cancer,
1216
metastatic hormone-refrac-
tory prostate cancer,
17
and advanced breast cancer.
18,19
Trabectedin is approved in Europe and many other coun-
tries for the treatment of patients with advanced STS
after failure or unsuitability of anthracyclines and/or
ifosfamide,
20
as well as in combination with pegylated
liposomal doxorubicin for patients with relapsed, plati-
num-sensitive ovarian carcinoma.
15
Trabectedin was noted early in clinical development to
demonstrate very relevant antitumour activity against myx-
oid-round cell liposarcoma (MRC-L-sarcoma).
21,22
Patho-
genesis of MRC-L-sarcoma is related to characteristic
chromosomal translocations, such as t(12;16)(q13;p11) or
less frequently t(12;22)(q13;q12), resulting in the expression
of FUS-DDIT3 and EWS- DDIT3 fusion genes, respec-
tively.
23
The high activity of trabectedin against MRC-L-
sarcoma seems to be related to its ability to counteract
the biological activity of the chimeric FUS-DDIT3 onco-
protein, a hallmark of this disease.
2426
In vitro studies
showed that the expression of dierent variants of the
FUS-DDIT3 fusion transcripts correlated with the sensitiv-
ity to trabectedin.
27
The FUS-DDIT3 oncoprotein acts as a
deregulated transcription factor, and trabectedin may inter-
fere with the binding of this fusion protein to specic DNA
promoters, causing altered expression of genes encoding
proteins such as PTX3 and IL-6.
25,28
Results with trabect-
edin from a retrospective series of patients with pretreated
MRC-L-sarcoma treated in compassionate use pro-
grams
3,21
showedthe t(12:16)(q13;p11) chromosomal trans-
location in a 33 of 51 patients. Type I, II, or IVFUS-DDIT3
fusion transcripts were found in patients responding to tra-
bectedin, while type III form, alone or together with type II,
was found in non-responders. Furthermore, in a phase II
exploratory clinical trial trabectedin administered as induc-
tion treatment in chemotherapy-na ve patients with a local-
ised resectable MRC-L-sarcoma resulted in several
pathological and molecular complete responses, i.e. com-
plete disappearance of tumour tissue at histopathological
evaluation as well as absence of cells with the FUS-DDIT3
translocation in the post-treatment surgical specimen.
29
The maturation observed in the malignant liposarcoma
cells, with transition of the residual spindle non-lipogenic
cells into mature signet-ring vacuolated lipoblasts,
was consistent with in vitro data showing that trabectedin
can remove dierentiation blockade mediated by the
FUS-DDIT3 chimera and induce adipocytic
dierentiation.
25
Based on the hypothesis that STS subtypes harbouring
fusion oncoproteins may have similar pathogenesis due
to aberrant transcription induced by the chimera, the
results observed in MRC-L-sarcoma could be extrapo-
lated to other translocation-related sarcomas (TRS). To
address this, we have conducted this retrospective pooled
analysis to assess the ecacy of trabectedin in several
subtypes of TRS.
2. Patients and methods
Trabectedin integrated database (PharmaMar,
Colmenar Viejo, Madrid, Spain) was examined using
pooled data from 81 adult patients with TRS who
received single-agent trabectedin in 8 multicentre phase
II clinical trials. Overall results from 7 of these 8 clinical
trials were previously published
911,20,3032
; the 81
patients evaluated here represent 10.5% of 771 STS
patients treated in these clinical trials. All of them had
histological conrmation of TRS and a life expectancy
P 3 months, a performance status 01, adequate renal,
hepatic and bone marrow function according to labora-
tory standard parameters, and complete recovery from
relevant toxicity derived from previous treatments. All
trials were carried out in accordance with the Declara-
tion of Helsinki, guidelines for Good Clinical Practice
and local regulations, and were approved by the institu-
tional review boards. In each clinical trial, informed
written consent was obtained from all patients.
2 A.L. Cesne et al. / European Journal of Cancer xxx (2012) xxxxxx
Antitumour activity was a primary study end-point in
these clinical trials, and safety was a secondary end-
point. Objective tumour response and progression-free
survival (PFS) were evaluated according to the World
Health Organisation (WHO) criteria
33
or to Response
Evaluation Criteria in Solid Tumours (RECIST)
v.1.0.
34
Patients were also followed for assessment of
overall survival (OS). Safety analyses were based on
the all treated population, dened as those patients
who received at least one part of one infusion. Adverse
events (AEs) were collected until 30 days after adminis-
tration of the last dose of study treatment. All AEs sus-
pected to be related to study treatment were followed
until the event or its sequelae resolved or stabilised at
an acceptable level to the Investigator and the Sponsor.
AEs were coded using the Medical Dictionary for Reg-
ulatory Activities (MedDRA) and graded according to
the National Cancer Institute Common Toxicity Crite-
ria (NCI-CTC), v. 1.0 or 2.0.
Non-continuous variables were described in frequency
tables using counts and percentages. Continuous variables
were described by median, minimumand maximumvalues.
3. Results
3.1. Patient characteristics
About half of patients were male, and median age
was 43 years (range, 1776 years) (Table 1). TRS sub-
types were synovial sarcoma (n = 45), MRC-L-sarcoma
(n = 27), alveolar soft part sarcoma (n = 4), endometrial
stromal sarcoma (n = 3) and clear cell sarcoma (n = 2).
All but one patient had received prior chemotherapy
(median of 2 lines; range, 04 lines). Prior lines included
anthracyclines (n = 6, 7%), ifosfamide (n = 1, 1%) or
both (n = 73, 90%). Trabectedin was administered as
second-line chemotherapy in 30 patients (37%), and as
third- or further-line in 50 patients (62%).
3.2. Trabectedin treatment
Trabectedin dose and schedules administered were
1.5 mg/m
2
as an intravenous 24-h infusion every 3 weeks
(q3wk) (n =43), 1.65/1.5/1.3 mg/m
2
as a 3-h infusion
q3wk (n = 24) and 0.58 mg/m
2
as a 3-h infusion weekly for
three consecutive weeks every 4 weeks (n =14). The patients
receivedamedianof 4cycles (range, 148cycles), witha med-
ian dose intensity of 0.40 mg/m
2
/week (range, 0.150.50 mg/
m
2
/week). Thirty-twopatients (40%) received P6 cycles and
16 patients (20%) received P10 cycles. The patients were on
trabectedin treatment for a median of 14 weeks (range, 3
181 weeks). Treatment discontinuations were due to disease
progression (n = 53, 65%), adverse events (n =7, 9%), or
other causes (n = 21, 26%).
3.3. Ecacy
A conrmed partial response occurred in 8 patients
(10%; 95% CI, 419%) (Table 2). Responses per TRS
Table 1
Characteristics of patients with translocation-related sarcomas treated
with trabectedin in 8 phase II clinical trials (n = 81).
n %
Age, median (range) 43 (1776)
Gender
Male 42 52
Female 39 48
Primary tumour
Synovial sarcoma 45 56
MRC-L-sarcoma 27 33
Alveolar soft part sarcoma 4 5
Endometrial stromal sarcoma 3 4
Clear cell sarcoma 2 3
ECOG performance status
0 49 60
1 32 40
Prior chemotherapy 80 99
Regimens (median, range) 2 (04)
Number of prior regimens
62 66 82
P2 15 18
Prior surgery 79 98
Prior radiotherapy 57 70
ECOG, Eastern Cooperative Oncology Group; MRC-L-sarcoma,
myxoid-round cell liposarcoma.
Table 2
Results of ecacy in translocation-related sarcomas: overall and per
tumour type.
Best objective response n %
Overall results (n = 81)
PR 8 10
SD 40 49
PD 30 37
NE 3 4
Results per tumour type
Synovial sarcoma (n = 45)
PR 3 7
SD 21 47
PD 19 42
NE 2 4
MRC-L-sarcoma (n = 27)
PR 4 15
SD 14 52
PD 8 30
NE 1 4
Alveolar soft part sarcoma (n = 4)
SD 4 100
Endometrial stromal sarcoma (n = 3)
PR 1 33
PD 2 67
Clear cell sarcoma (n = 2)
SD 1 50
PD 1 50
MRC-L-sarcoma, myxoid-round cell liposarcoma; NE, non-evaluable;
PD, progressive disease; PR, partial response; SD, stable disease.
A.L. Cesne et al. / European Journal of Cancer xxx (2012) xxxxxx 3
subtype were as follows: MRC-L-sarcoma, n = 4 (15%;
95% CI, 434%); synovial sarcoma, n = 3 (7%; 95%
CI, 118%) and low-grade endometrial stromal sar-
coma, n = 1 (33%; 95% CI, 0.191%).
Stable disease (SD) was noted as best response in 40
patients (49%), as follows: synovial sarcoma, n = 21
(47%); MRC-L-sarcoma, n = 14 (52%); alveolar soft
part sarcoma (100%), n = 4 and clear cell sarcoma,
n = 1 (50%). Therefore, tumour control rate (PR plus
SD) was 59% (48 of 81 treated patients), 95% CI,
4870%. SD P4 months was found in 27 patients
(33%) and SD P6 months in 20 patients (25%). Pro-
gression-free rate at 2 months (PR plus SD P2 months)
was 57% (n = 46 patients).
Median PFS in all TRS subtypes was 4.1 months
(95% CI, 2.86.1 months), with 6-month PFS rate of
40% (95% CI, 2951%). PFS results per TRS subtype
are shown in Fig. 1 (per patient).
Fig. 2A shows the KaplanMeier plot for PFS in all
TRS and in the two more frequent TRS subtypes: syno-
vial sarcoma and MRC-L-sarcoma. In patients with
synovial sarcoma, median PFS was 3.0 months (95%
CI, 1.64.1 months), with 6-month PFS rate of 22%
(95% CI, 934%). In patients with MRC-L-sarcoma,
median PFS was 9.0 months (95% CI, 5.611.9 months),
with 6-month PFS rate of 64% (95% CI, 4583%).
Median OS was 17.4 months (95% CI,
11.123.2 months), with survival rate at 24 months of
35% (95% CI, 2447%). Fig. 2B shows the KaplanMeier
plot for OS in all TRS, synovial sarcoma and MRC-L-
sarcoma. In patients with synovial sarcoma, median OS
was 13.9 months (95% CI, 7.219.4 months), with 24-
month survival rate of 28% (95% CI, 1343%). In patients
with MRC-L-sarcoma, median OS was 18.3 months (95%
CI, 10.533.6 months), with
24-month survival rate of 41% (95% CI, 2259%).
Since a superior disease control in liposarcomas and
leiomyosarcomas was observed with the 24-h q3wk tra-
bectedin regimen with respect to the 0.58 mg/m
2
3-h
weekly for three consecutive weeks every 4 weeks regi-
men in the pivotal clinical trial for approval of trabect-
edin in STS
20
, a retrospective analysis of the results in
patients with MRC-L was done (n = 13 patients treated
with the 24-h q3wk regimen and n = 14 patients treated
with the weekly regimen). All 4 PRs in MRC-L were
found with the 24-h q3wk schedule. With the caveat of
the low number of patients analysed, PFS and OS were
remarkably longer with the 24-h q3wk regimen. Median
PFS was 11.9 months (95% CI, 8.520.5 months) (24-h
q3wk) versus 5.6 months (95% CI, 2.110.5 months)
(weekly) and median OS was 34.4 months (95% CI,
18.337.8 months) (24-h q3wk) versus 10.5 months
(95% CI, 4.023.2 months) (weekly).
3.4. Safety
Safety was evaluated in all 81 patients who received a
total of 477 cycles of trabectedin. Consistent with the
Fig. 1. Progression-free survival by translocation-related sarcoma subtype and patient.
known safety prole of trabectedin, the most common
grade 34 AEs related to trabectedin were neutropenia
(n = 47 patients; 59%) and transaminase increases
(ALT, n = 37, 46%; AST, n = 29, 37%) (Table 3). Severe
neutropenia was transient, with short duration (82% of
grade 34 episodes had a duration of (5 days), rapid
recovery (79% of cases returned to grade 6 2 before
Day 28) and no adverse clinical eects (i.e. no infection
or symptoms). In six cycles (6/477 = 1%), 5 patients
experienced an episode of febrile neutropenia. Severe
increases in circulating levels of transaminases were also
transient, asymptomatic and not cumulative, in most
cases returning to grade 1 before administration of the
subsequent cycle (76% before Day 21, and 24% before
Day 28 for ALT; 96% before Day 21 and 4% before
Day 28 for AST). Two patients (4%) had grade 3/4
CPK; no cases of rhabdomyolysis were reported.
4. Discussion
Trabectedin has demonstrated antitumour activity
and clinical benet in multiple dierent histological sub-
types of STS. Ecacy results in liposarcomas and leio-
myosarcomas shown in a pivotal randomised phase II
clinical trial, together with results of prior single-arm
phase II trials which included other sarcoma types,
served as the basis for regulatory approval of trabectedin
in advanced STS.
911,20
Based on the ecacy results of
Fig. 2. KaplanMeier plot of progression-free survival (3A) and overall survival (3B) in all translocation-related sarcomas (n = 81), synovial
sarcoma (n = 45) and myxoid-round cell liposarcoma (MRC-L-sarcoma) (n = 27).
trabectedin in a retrospective series of patients with pre-
treated MRC-L-sarcoma,
21,22
and considering the likely
functional similarities of the fusion oncoproteins of
MRC-L-sarcomas with those of other TRS, a retrospec-
tive analysis of trabectedin activity in dierent TRS sub-
types was performed. This analysis shows a 10% ORR,
with 59% tumour control rate in patients with several
TRS subtypes. Results from a retrospective analysis of
620 patients with all STS subtypes (including 8590%
of patients with STS without pathognomonic transloca-
tions as well as 1015% of patients with TRS) treated
with trabectedin in clinical trials during the clinical devel-
opment of this agent showed lower gures: 7% ORR and
49% tumour control rate.
35
Median PFS in TRS was
4.1 months, 40% of patients were progression-free after
6 months, median survival was 17.4 months, and 35%
of patients were alive after 2 years from treatment start.
The corresponding data for the time-to-event variables in
the retrospective analysis of all STS subtypes also
showed lower gures: median PFS of 2.3 months, 27%
of patients free of progression after 6 months, median
survival of 13.0 months and 30% of patients alive after
2 years.
35
Comparison of KaplanMeier curves of PFS
and survival are shown in Fig. 3A and B, respectively.
In the current study, PFS rates at 6 months in all TRS
(40%), but also in the two more frequent TRS subtypes
(22% in synovial sarcoma and 64% in MRC-L-sarcoma)
notably exceeded the cuto of 14% proposed by the Soft
Tissue and Bone Sarcoma Group of the European Orga-
nisation for Research and Treatment of Cancer
(EORTC-STBSG) to consider a therapy as active in pre-
treated STS.
36
The present results extend the previously
reported high activity of trabectedin in MRC-L-sarco-
mas to other TRS subtypes in which partial responses
or disease control have been documented, such as syno-
vial sarcoma, alveolar soft part sarcoma, endometrial
stromal sarcoma, or clear cell sarcoma. Although new
agents have shown activity in some TRS subtypes, such
as the third generation aromatase inhibitor letrozole
for the treatment of low grade endometrial stromal
sarcoma
37
, the vascular endothelial growth factor
(VEGF)-receptor and multi-kinase inhibitor pazopanib
for synovial sarcoma
38
or in non-selected STS after fail-
ure of 24 lines of chemotherapy
39
, the tubulin-targeting
eribulin for synovial sarcoma
40
, or the selective VEGF
receptor inhibitor cediranib in alveolar soft part sar-
coma
41
, the results observed in this analysis conrm tra-
bectedin as a valid therapeutic option with a potential of
prolonged disease control and OS in patients with
advanced TRS. Partial responses have been previously
reported in clinical trials or retrospective series evaluat-
ing trabectedin in patients with TRS such as synovial sar-
coma,
4245
desmoplastic small round cell tumour
46
or
Ewings sarcoma.
4749
In the latter case, activity was
explained by blockage of the EWSR1-FLI1 fusion onco-
protein, an aberrant transcription factor.
47
These results
support the hypothesis that trabectedin might act as to
inhibit interaction of aberrant transcription factors
derived from chromosomal translocations with tumour
cell DNA in these sarcoma subtypes.
50,51
A higher
expression of the DNA repair genes ERCC1 and XPG,
which has been demonstrated in TRS versus non-TRS
sarcomas
52
and in non-selected STS
53
, may also contrib-
ute to the higher sensitivity and better outcomes of TRS
to trabectedin treatment.
Trabectedin is generally well tolerated, with low rates
of drug-related treatment discontinuations.
920
As
expected, the most common adverse events were tran-
sient transaminase increases and reversible neutropenia,
both with very limited clinical consequences and 40%
and 20% of patients received P6 and 10 cycles, respec-
tively. This supports the fact that trabectedin is suitable
to be administered for prolonged periods (up to 59
cycles) in patients who show benet with disease control
or tumour shrinkage.
54
In conclusion, trabectedin shows denite antitumour
activity in STS with particularly interesting levels of dis-
ease control in TRS subtypes. Previous studies did not
prospectively analyse the correlation of response to tra-
bectedin with the fusion oncoprotein present in each
patient, according to the dierent sarcoma subtypes,
and molecular characterisation was not centralised. A
randomised phase III trial to compare the ecacy and
safety of trabectedin versus doxorubicin-based chemo-
therapy in patients with TRS as rst-line therapy is
ongoing (ClinicalTrials.gov identier NCT00796120).
The clinical outcomes of the patients in relation to the
fusion oncoprotein types and molecular variants will
Table 3
Worst grade per patient of trabectedin-related adverse events in
translocation-related sarcomas.
Adverse event
a
Grade 1/2 Grade 3 Grade 4
n % n % n %
Haematological
Anaemia
*
66 83 7 9 2 3
Febrile neutropenia 3 4 2 3
Neutropenia
*
16 20 26 33 21 26
Thrombocytopenia*
*
25 32 12 15 4 5
Non-haematological
AP increase
*
31 39 1 1
ALT increase
*
35 44 22 28 15 19
AST increase
**
40 51 25 32 4 5
Bilirubin increase
*
25 31 1 1
CPK increase
***
19 35 1 2 1 2
Fatigue 49 61 3 4
Nausea 41 51 5 6
Vomiting 23 28 6 7
AP, alkaline phosphatase; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; CPK, creatine phosphokinase.
a
Adverse events that reached only grade 1 or 2 are not shown.
*
n = 80.
**
n = 79.
***
n = 55.
be analysed and molecular work will be done in a central
facility.
Conict of interest statement
A. Le Cesne received honoraria from PharmaMar.
R.G. Maki received research support and consulting
fees (participation in data safety monitoring board)
from PharmaMar. J.Y. Blay received research support
and honoraria from PharmaMar. P. Lardelli, V. Alfaro
and A. Nieto are employees of PharmaMar. P Lardelli
and A. Nieto own stock of PharmaMar. G. D. Demetri
received research support to Dana-Farber Cancer
Institute for specic clinical trial agreements in the
sarcoma unit, honoraria as consultant and uncompen-
sated regulatory presentation support from Johnson &
Johnson.
Acknowledgements
Financial support for this analysis was provided by
PharmaMar, Madrid, Spain.
This study was presented at the 2009 ECCO 1534th
ESMO Multidisciplinary Congress 2009. Le Cesne A,
Gianni L, Maki R, Blay JY, Verweij J, Poveda A, et al.
Fig. 3. KaplanMeier plot of progression-free survival (4A) and overall survival (4B) in translocation-related sarcomas (TRS) (n = 81) and pooled
data from a retrospective analysis of 620 patients with all soft tissue sarcoma (STS) subtypes (including TRS but also non-TRS) treated with
trabectedin in clinical trials during the clinical development of this agent (drawn from
35
). As data from all STS included several of the TRS cases
evaluated here, no formal statistical comparison was done.
Translocation-related sarcomas (TRS): a retrospective
analysis of activity with trabectedin. Abstract E15-0894.
References
1. Mitelman F. Recurrent chromosome aberrations in cancer. Mutat
Res 2000;462(23):24753.
2. Antonescu CR. The role of genetic testing in soft tissue sarcoma.
Histopathology 2006;48(1):1321.
3. American Cancer Society-Statistics-Cancer Facts and Figures,
Soft tissue sarcoma. <http://www.cancer.org>; 2004.
4. Mertens F, Antonescu CR, Hohenberger P, et al. Translocation-
related sarcomas. Semin Oncol 2009;36(4):31223.
5. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of
adults: state of the translational science. Clin Cancer Res
2003;9(6):194156.
6. Xia SJ, Barr FG. Chromosome translocations in sarcomas and the
emergence of oncogenic transcription factors. Eur J Cancer
2005;41(16):251327.
7. Ladanyi M, Bridge JA. Contribution of molecular genetic data to
the classication of sarcomas. Hum Pathol 2000;31(5):5328.
8. Verweij J, Baker LH. Future treatment of soft tissue sarcomas will
be driven by histological subtype and molecular aberrations. Eur J
Cancer 2010;46(5):8638.
9. Garcia-Carbonero R, Supko JG, Manola J, et al. Phase II and
pharmacokinetic study of ecteinascidin 743 in patients with
progressive sarcomas of soft tissues refractory to chemotherapy.
J Clin Oncol 2004;22(8):148090.
10. Yovine A, Riofrio M, Blay JY, et al. Phase II study of
ecteinascidin-743 in advanced pretreated soft tissue sarcoma
patients. J Clin Oncol 2004;22(5):8909.
11. Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in
advanced soft tissue sarcomas: a European Organisation for the
Research and Treatment of Cancer (EORTC) soft tissue and bone
sarcoma group trial. J Clin Oncol 2005;23(3):57684.
12. Sessa C, De Braud F, Perotti A, et al. Trabectedin for women with
ovarian carcinoma after treatment with platinum and taxanes fails.
J Clin Oncol 2005;23(9):186774.
13. Del Campo JM, Roszak A, Bidzinski M, et al. Phase II
randomized study of trabectedin given as two dierent every 3
weeks dose schedules (1.5 mg/m
2
24 h or 1.3 mg/m
2
3 h) to patients
with relapsed, platinum-sensitive, advanced ovarian cancer. Ann
Oncol 2009;20(11):1794802.
14. Krasner CN, McMeekin DS, Chan S, et al. A Phase II study of
trabectedin single agent in patients with recurrent ovarian cancer
previously treated with platinum-based regimens. Br J Cancer
2007;97(12):161824.
15. Monk BJ, Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated
liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol
2010;28(19):310714.
16. Monk BJ, Herzog TJ, Kaye SB, et al. Final survival results of the
randomized phase III study of trabectedin with pegylated liposo-
mal doxorubicin (PLD) versus PLD in recurrent ovarian cance. J
Clin Oncol 2011;29(Suppl.) [abstract 5046].
17. Michaelson MD, Gilligan T, Oh W, et al. Phase II study of three
hour, weekly infusion of trabectedin (ET-743) in men with
metastatic, androgen-independent prostate carcinoma (AIPC). J
Clin Oncol, ASCO Annual Meeting Proceedings 2005;23(No. 16S,
Part I of II June 1 Suppl.):4517.
18. Gurtler JS, Goldstein L, Delprete S, et al. Trabectedin in third line
breast cancer: A multicenter, randomized, phase II study comparing
two administration regimens. J Clin Oncol, ASCO Annual meeting
proceedings 2005;23(No. 16S, Part I of II June 1 Suppl.):625.
19. Zelek L, Yovine A, Brain E, et al. A phase II study of
Yondelis((R)) (trabectedin, ET-743) as a 24-h continuous intrave-
nous infusion in pretreated advanced breast cancer. Br J Cancer
2006;94(11):16104.
20. Demetri GD, Chawla SP, von Mehren M, et al. Ecacy and safety
of trabectedin in patients with advanced or metastatic liposarcoma
or leiomyosarcoma after failure of prior anthracyclines and
ifosfamide: results of a randomized phase II study of two dierent
schedules. J Clin Oncol 2009;27(25):418896.
21. Grosso F, Jones RL, Demetri GD, et al. Ecacy of trabectedin
(ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a
retrospective study. Lancet Oncol 2007;8(7):595602.
22. Grosso F, Sanlippo R, Virdis E, et al. Trabectedin in myxoid
liposarcomas (MLS): a long-term analysis of a single-institution
series. Ann Oncol 2009;20(8):143944.
23. Sandberg AA. Updates on the cytogenetics and molecular genetics
of bone and soft tissue tumors: liposarcoma. Cancer Genet
Cytogenet 2004;155(1):124.
24. DIncalci M, Galmarini CM. A review of trabectedin (ET-743): a
unique mechanism of action. Mol Cancer Ther 2010;9(8):215763.
25. Forni C, Minuzzo M, Virdis E, et al. Trabectedin (ET-743)
promotes dierentiation in myxoid liposarcoma tumors. Mol
Cancer Ther 2009;8(2):44957.
26. Casali PG, Sanlippo R, DIncalci M. Trabectedin therapy for
sarcomas. Curr Opin Oncol 2010;22(4):3426.
27. Grosso F, Forni C, Frapolli R, et al. Sensitivity of myxoid-round
cell liposarcoma (MRCL) to trabectedin (T) may be related to a
direct eect on the fusion transcript. J Clin Oncol, ASCO Annual
Meeting Proceedings Part I 2007;25(18S):0000.
28. Germano G, Frapolli R, Simone M, et al. Antitumor and anti-
inammatory eects of trabectedin on human myxoid liposarcoma
cells. Cancer Res 2010;70(6):223544.
29. Gronchi A, Bui BN, Bonvalot S, et al. Phase II clinical trial of
neoadjuvant trabectedin in patients with advanced localized
myxoid liposarcoma. Ann Oncol 2011. http://dx.doi.org/10.1093/
annonc/mdr265.
30. Paz-Ares L, Lopez-Pousa A, Poveda A, et al. Trabectedin in pre-
treated patients with advanced or metastatic soft tissue sarcoma: a
phase II study evaluating co-treatment with dexamethasone. Invest
New Drugs 2012;30(2):72940.
31. Garcia-Carbonero R, Supko JG, Maki RG, et al. Ecteinascidin-
743 (ET-743) for chemotherapy-naive patients with advanced soft
tissue sarcomas: multicenter phase II and pharmacokinetic study.
J Clin Oncol 2005;23(24):548492.
32. Demetri GD, Manola J, Harmon D, et al. Ecteinascidin-743 (ET-
743) Induces Durable Responses and Promising 1-Year Survival
Rates in Soft Tissue Sarcomas (STS): Final Results of Phase II and
Pharmacokinetic Studies in the U.S.A.. Proc Am Soc Clin Oncol,
ASCO Annual Meeting 2001;20:1406.
33. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting
results of cancer treatment. Cancer 1981;47(1):20714.
34. Therasse P, Arbuck SG, Eisenhauer EA, et al. New Guidelines to
Evaluate the Response to Treatment in Solid Tumors. J Natl
Cancer I 2000;92(3):20516.
35. Demetri GD, Blay J, Schoski P, et al. Outcomes of patients (pts)
with advanced soft-tissue sarcomas (STS) treated in clinical trials
(CTs) versus expanded access programs (EAPs): A decade of
experience with single-agent trabectedin (Tr). J Clin Oncol
2010;705(15 Suppl.):20516 [abstract No. 10029].
36. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al.
Prognostic factors for the outcome of chemotherapy in advanced
soft tissue sarcoma: an analysis of 2185 patients treated with
anthracycline-containing rst-line regimens-a European Organi-
zation for Research and Treatment of Cancer Soft Tissue and
Bone Sarcoma Group Study. J Clin Oncol 1999;17(1):1507.
37. Maluf FC, Sabbatini P, Schwartz L, Xia J, Aghajanian C.
Endometrial stromal sarcoma: objective response to letrozole.
Gynecol Oncol 2001;82(2):3848.
38. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase
angiogenesis inhibitor, in patients with relapsed or refractory
advanced soft tissue sarcoma: a phase II study from the European
organisation for research and treatment of cancer-soft tissue and
bone sarcoma group (EORTC study 62043). J Clin Oncol
2009;27(19):312632.
39. Van Der Graaf T, Blay J, Chawla SP, et al. PALETTE: A
randomized, double-blind, phase III trial of pazopanib versus
placebo in patients (pts) with soft-tissue sarcoma (STS) whose
disease has progressed during or following prior chemotherapy
An EORTC STBSG Global Network Study (EORTC 62072). J
Clin Oncol 2011;29(2011 (Suppl.)) [abstr LBA10002].
40. Schoski P, Ray-Coquard IL, Cio A, et al. Activity of eribulin
mesylate in patients with soft-tissue sarcoma: a phase 2 study in
four independent histological subtypes. Lancet Oncol
2011;12(11):104552.
41. Kummar S, Strassberger A, Monks A, et al. An evaluation of
cediranib as a new agent for alveolar soft part sarcoma (ASPS). J
Clin Oncol 2011;29(2011 (Suppl.)) [abstract 10001].
42. Grosso F, Dileo P, Sanlippo R, et al. Steroid premedication
markedly reduces liver and bone marrow toxicity of trabectedin in
advanced sarcoma. Eur J Cancer 2006;42(10):148490.
43. Grosso F, Jones RL, Blay JY, et al. Trabectedin (T) in Soft
Tissue Sarcomas (STS) Carriying a Chromosomal Transloca-
tion: an Exploratory Analysis. In: 13th Annual Conective Tissue
Oncology Society meeting proceedings, Seattle, WA; 2007,
Abstract 900.
44. Chawla T, Mohan V, Chua V, et al. A phase II study of Yondelis
(ET-743, Tracectidin) in advanced/metastatic soft-tissue sarcoma. In:
13th CTOS annual meeting 2007, November 13, Seattle, WA; 2007.
45. Dileo P, Sanlippo R, Grosso F, et al. Trabectedin (T) in
advanced, pretreated synovial sarcomas (SS): A retrospective
analysis of 39 patients (pts) from three European institutions. J
Clin Oncol, ASCO American Society of Clinical Oncology, 46th
Annual Meeting 2010;28(15 Suppl.):705 [abstract 10030].
46. Lopez-Gonzalez A, Cantos B, Tejerina E, Provencio M. Activity
of trabectidin in desmoplastic small round cell tumor. Med Oncol
2010. http://dx.doi.org/10.1007/s12032-010-9687-9.
47. Grohar PJ, Grin LB, Yeung C, et al. Ecteinascidin 743 interferes
with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia
2011;13(2):14553.
48. Roylance R, Seddon B, McTiernan A, et al. Experience of the use
of trabectedin (ET-743, Yondelis) in 21 patients with pre-treated
advanced sarcoma from a single centre. Clin Oncol (R Coll Radiol)
2007;19(8):5726.
49. Dileo P, Grosso F, Casanova M, et al. Trabectedin (T) in
metastatic Ewings family tumors (EFT) patients (pts) progressing
after standard chemotherapy. J Clin Oncol, ASCO Annual Meeting
Proceedings Part I 2007;25(18s):10040.
50. Minuzzo M, Marchini S, Broggini M, et al. Interference of
transcriptional activation by the antineoplastic drug ecteinascidin-
743. Proc Natl Acad Sci U S A 2000;97(12):67804.
51. Jin S, Gorfajn B, Faircloth G, Scotto KW. Ecteinascidin 743, a
transcription-targeted chemotherapeutic that inhibits MDR1
activation. Proc Natl Acad Sci U S A 2000;97(12):67759.
52. Le Cesne A, Taron M, Rosell R, et al. Biomarkers of DNA repair
eciency in translocation related sarcoma (TRS) patients treated
with trabectedin (T). In: CTOS Connective Tissue Oncology
Society 16th annual meeting. Paris, France; 2010.
53. Schoski P, Taron M, Jimeno J, et al. Predictive impact of DNA
repair functionality on clinical outcome of advanced sarcoma
patients treated with trabectedin: a retrospective multicentric
study. Eur J Cancer 2011;47(7):100612.
54. Le Cesne A, Yovine A, Blay JY, et al. A retrospective pooled
analysis of trabectedin safety in 1132 patients with solid tumors
treated in phase II clinical trials. Invest New Drugs 2011.

Et 743 1606

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Et 743 1606

Uploaded by

Copyright:

Available Formats

A retrospective analysis of antitumour activity with trabectedin

You might also like