Efficacy and Safety Assessment of Oral LBH589 in Adult Patients With Advanced Soft Tissue Sarcoma After Pre-treatment Failure: an Open-label, Multicenter Phase II Study
Despite surgical excision and radiation therapy, approximately 50% of patients treated for
localised STS will experience local or distant relapse.
Recurrent STS : current therapeutic strategies Although some patients may be salvaged with
surgery, chemotherapy using doxorubicin-based regimens is in most cases indicated for
patients with recurrent STS. Progression-free survival (PFS) is in most cases less than or
equal to 6 months. Most patients die of their disease within 12-15 months following the
diagnosis of advanced disease. Doxorubicin is considered as the standard of care in the
first line setting for patients with locally advanced unresectable or metastatic STS.
However, only 15-25% of these patients exhibit objective response following this
chemotherapy while 30-35% experiment rapid disease progression. Doxorubicin-based
combinations have resulted in an inconsistent increase in response rate but no survival
advantage versus single-agent doxorubicin. After doxorubicin-based regimens failure, most
agents, including other agents approved for the treatment of STS such as dacarbazine,
ifosfamide and trabectedin, have shown very low response rates and short PFS. The only
approved agent in this setting is trabectedin, which has shown prolonged stabilization in
approximately 20% of patients at 6 months in several phase II trials. Gemcitabine-docetaxel
combination, although not approved for the treatment of STS has shown interesting response
rates in leiomyosarcomas, as well as other STS subtypes . Mechanisms of chemoresistance are
poorly understood.
Place of LBH589:
LBH589 is postulated to have activity in sarcomas by being able to arrest gene transcription
through the inhibition of HDAC, to cause the misfolding of important proteins for sarcoma
biology such as fusion proteins or overexpressed genes (HDM2, cdk4, AKT…) via the disruption
of HSP90 functioning . Some mechanisms similar to leukemia-associated fusion proteins, which
have been shown to recruit HDAC to repress hematopoietic differentiation, might be involved
by some translocation-associated sarcomas. The SYT portion of the synovial sarcoma
oncoprotein SYT-SSX interacts with trithorax-group proteins and binds directly to the mSin3A
HDAC component. SSX associates with polycomb-group proteins, which involve HDAC activity to
mediate transcriptional repression; thus, aberrant epigenetic changes in gene expression
seem to be a central effect of the fusion oncoprotein in this disease. HDAC inhibitors have
been effective against both synovial sarcoma and Ewing sarcoma in preclinical studies .
Evidence has also been presented for growth inhibition and induction of differentiation in
clear cell sarcoma (Nielsen TO, Vancouver Coastal Health Research Institute, Vancouver,
Canada, unpublished data) and chondrosarcoma by HDACi.
Data from the phase I study involving patients with advanced solid tumors indicate that the
MWF every week schedule of LBH589 is pharmacodynamically and clinically active. Histone
acetylation was detected in peripheral blood cells for up to 72 hours (the maximum duration
between doses on the MWF every week schedule) in 50% of patients at the 20 mg and 30 mg
doses and CR and PR were observed in two and three patients respectively, with cutaneous
T-cell lymphoma. Grade 3 fatigue was the dose-limiting toxicity (DLT) in 2 patients treated
at the 40 mg level and 1 patient treated at the 60 mg level. The 40 mg level seem to be
tolerable and is felt to be the most likely to have activity in solid tumors.
After first-line chemotherapy failure, efficacy of therapeutic alternatives is limited. The
purpose of this trial is therefore to investigate the efficacy, safety and tolerability of
40 mg of LBH589 given orally on a twice a week.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
3 months non progression rate
3 months
No
BLAY PR Jean-Yves
Principal Investigator
Centre Léon Berard
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
ESTIM-LBH
NCT01136499
January 2010
January 2013
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