Efficacy and Safety Assessment of Oral LBH589 in Adult Patients With Advanced Soft TIssue Sarcoma After Pre-treatment Failure (ESTIM-LBH)
The purpose of this study is to assess efficacy and safety of LBH589 - Panobinostat®, a potent HDACi, in patients with advanced STS who experiment disease progression after or during first-line chemotherapy. The rational is based on the observation of activity of deacetylase inhibitor (DACi) in several pre-clinical models of STS including Synovial sarcoma and Ewing sarcoma.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- 3 months non progression rate [ Time Frame: 3 months ] [ Designated as safety issue: No ]
- Progression-free survival (PFS) [ Time Frame: 6 months after the end of treatment (18 months after the start of treatment) ] [ Designated as safety issue: No ]
- Time to progression (TTP) [ Time Frame: 6 months after the end of treatment (18 months after the start of treatment) ] [ Designated as safety issue: No ]
- best objective response rate [ Time Frame: 6 months after the end of treatment (18 months after the start of treatment) ] [ Designated as safety issue: No ]
- Safety profile based on incidence, intensity and type of adverse events [ Time Frame: 6 months after the end of treatment (18 months after the start of treatment) ] [ Designated as safety issue: No ]clinically significant changes in patients physical examination findings; vital sign measuremments; and clinical laboratory results will be recorded and monitored.
- Plasmatic rate of LBH589 [ Time Frame: 6 months after the end of treatment (18 months after the start of treatment) ] [ Designated as safety issue: No ]assess steady-state pharmacokinetics of the new formulation of LBH589 versus that one used in phase one studies.
|Study Start Date:||January 2010|
|Study Completion Date:||January 2013|
|Primary Completion Date:||January 2012 (Final data collection date for primary outcome measure)|
Experimental: LBH PANOBINOSTAT
40 mg 3 days per week
Drug: LBH589 (Panobinostat®)
40 mg MWF.
40 mg of LBH589, orally administered on Monday, Wednesday and Friday (MWF) on a weekly schedule, until tumor progression or unacceptable toxicity.
Other Name: panobinostat
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.