Maintenance therapy with trabectedin versus observation after first line treatment with doxorubicin of patients with advanced or metastatic soft tissue sarcoma

1 Background and introduction
Soft Tissue Sarcoma (STS) is a rare group of heterogeneous mesenchymal cancers
originating from connective tissue. There are multiple histological subtypes of
STS. At present all these subtypes are usually grouped under the heading of STS
for the purpose of treatment, although an increasing number of new treatment
options are expected to be directed more specifically at individual
histological subtypes.
The annual incidence of STS is around 2-3/100,000. Overall, STS account for
approximately 1% of all malignancies, while they give rise to 2% of the total
cancer-related mortality. The 5-year survival in Europe for adult STS
(excluding visceral STS) averages 60%, with substantial geographic variations
(Ref. 1). The median survival time in patients with metastatic STS is usually <
12 months, and only a small subgroup of patients may achieve long term survival.
Surgery is usually the first line of management for localised disease. Standard
treatment is generally a wide surgical excision or even more radical surgery of
the primary tumor combined with adjuvant radiotherapy in selected cases. The
addition of post-operative radiotherapy appears to reduce the rate of local
recurrence (Ref. 2). However, even optimal local treatment does not prevent the
occurrence of distant metastases in many patients, especially those with
high-grade tumors. Although the effect of adjuvant chemotherapy has been
studied by several groups, the efficacy in most subtypes of STS is debatable.
An international meta-analysis indicated an effect of adjuvant systemic
treatment on progression free survival but did not show a significant effect on
overall survival (OS) (Ref. 3).
STS metastasizes primarily to the lungs but also to bone, liver and other
organs, depending on the subtype. Chemotherapy is widely used in the treatment
of unresectable advanced disease, basically with palliative intent, as most
initially chemotherapy-sensitive patients will ultimately relapse and present
at that point with chemotherapy-resistant disease.
Doxorubicin is the most active drug for the systemic treatment of STS. The
cumulative response rate in non-pretreated patients is 23% (15-30 %) (Ref. 4).
The use of doxorubicin treatment is limited due to its risk of cumulative
cardiotoxicity. Another active agent is ifosfamide. In a randomized Phase II
trial, single-agent ifosfamide achieved a 25% response rate in non-pretreated
patients (Ref. 5), but these results could later not be confirmed in an EORTC
phase III study. A third drug with marginal activity is dacarbazine (DTIC), but
its clinical relevance in STS is doubtful.
response rates than single agent doxorubicin. However, even if present, this
higher objective response rate did not translate into improved overall
survival. The involved trials compared various combinations such as CYVADIC
(cyclophosphamide, vincristine, doxorubicin, and DTIC), AI (doxorubicin and
ifosfamide), MAID (mesna, doxorubicin, ifosfamide and DTIC) or MAP (mitomycin
C, doxorubicin, and cisplatin) with single-agent doxorubicin. In all trials
single agent doxorubicin yielded less toxicity than the combination studied.
Thus, single-agent doxorubicin is currently still regarded as standard
treatment for the majority of adult patients with metastatic, unresectable STS,
with the exception of certain well-defined subtypes of sarcoma, such as
rhabdomyosarcoma, Ewing sarcoma of soft tissue and gastrointestinal stromal
tumor (GIST).
New treatment options are urgently required. The EORTC STBSG has already
evaluated several new drugs given as second line chemotherapy, but the vast
majority of these were found to be inactive, with the exception of agents such
as trabectedin (Ref. 6) or pazopanib (Ref. 7). Activity of gemcitabine combined
with docetaxel was observed in leiomyosarcoma and undifferentiated high-grade
pleomorphic sarcoma
After many years of research, the prognosis of advanced or metastatic soft
tissue sarcoma patients remains dismal. A recently published study by our group
on first-line treatment in 455 patients, treated with either doxorubicin alone
or doxorubicin in combination with ifosfamide reported median progression free
survival (PFS) of 4.6 months [95% CI 2.9*5.6] and 7.4 months [95% CI 6.6*8.3]
respectively, and a median overall survival of 12.8 months [95.5% CI 10.5*14.3]
in the doxorubicin group vs 14.3 months [12.5*16.5] in the doxorubicin and
ifosfamide group (Ref. 9).
According to data on approximately 1000 patients in the EORTC STBSG
retrospective database who received doxorubicin as first line treatment of
advanced or metastatic soft tissue sarcoma in the context of clinical trials
performed by the STBSG over the last 30 years, only about 35% of patients
completed at least 6 cycles of doxorubicin without signs of progression at the
end of their treatment. The PFS of these patients after completing the
first-line treatment was approximately 3 months, regardless of histological
subtype.
Maintenance therapy in advanced or metastatic soft tissue sarcoma is an
attractive option because of this short median PFS: a situation similar to
stage IV colorectal and non-small cell lung cancer where this concept has been
developed. Continuation of doxorubicin is not an option because of increasing
risk of cardiotoxicity beyond 6 cycles. We chose trabectedin (see below) as a
suitable candidate for maintenance after doxorubicin because it has no
cumulative toxicity and prolonged treatment, even beyond 10 cycles has proven
to be feasible in later lines of therapy. The intended dose of trabectedin will
be decreased and the interval prolonged from 3 to 4 weeks in order to avoid
risk of febrile neutropenia as much as possible, to stimulate adherence and to
maintain quality of life.

The main objective of the trial is to evaluate whether maintenance trabectedin
given after 6 cycles of doxorubicin first-line therapy for advanced or
metastatic STS prolongs progression-free survival (PFS) as compared to an
observational approach.
Secondary objectives are:
* To assess the treatment safety and tolerability
* To assess the efficacy of the treatment in terms of overall survival
(determined from randomization)
* To assess the time to second progression
* To compare the quality of life in patients randomized to the two study arms

This is a prospective, multicenter, randomized, open label Phase III trial
investigating whether a maintenance treatment with trabectedin, as compared to
the observational approach, can prolong progression-free survival in patients
with advanced, inoperable and/or metastatic STS after response or stabilisation
during first line treatment with doxorubicin.
In this trial, within 6 weeks after the last administration of doxorubicin, 90
patients will be centrally allocated by the randomization system in a 1:1 ratio
to either:
* Arm A (investigational treatment): Trabectedin 1.2 mg/m² through a central
venous catheter as an IV infusion over 24 hours every 4 weeks until disease
progression (RECIST 1.1) or unacceptable toxicity
* Arm B: Observation through clinical and radiological follow-up until disease
progression (RECIST 1.1).
Patients may receive commercial trabectedin after progression in arm B as
second line treatment as per investigator's decision.
Maintenance treatment is to be started within 3 days from randomization.
Randomization will be stratified by histology (L- versus non L-sarcoma)*.
* L-sarcoma: lipo- and leiomyosarcoma
Histopathology will be reviewed retrospectively by reference pathologists.

trabectedin a 4 weeks

The dose and interval of trabectedine are amended in such a way that we don't
expect any severe side effects