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Soft Tissue SarcomaPhase 2ESTIM-LBHNCT01136499

Efficacy and Safety Assessment of Oral LBH589 in Adult Patients With Advanced Soft TIssue Sarcoma After Pre-treatment Failure

A Phase 2 study testing LBH589 (Panobinostat®) in people with Soft Tissue Sarcoma, run by Centre Leon Berard at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Soft Tissue Sarcoma
What is being tested?
LBH589 (Panobinostat®)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
53 participants
Where
1 siteFrance
Study dates
Jan 2010to Jan 2013
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age ≥ 18 years.
  • Histologically proven advanced metastatic or unresectable soft tissue sarcoma, excluding osteosarcoma.
  • Prior treatment with a doxorubicin containing regimen whether in the adjuvant setting or for metastatic/advanced disease. If doxorubicin was given as adjuvant therapy patient may be included if relapse occurs within a year of adjuvant therapy. If relapse occurs more than one year after the completion of adjuvant therapy, the patient must have received one prior regimen for metastatic disease. Patient may have received one or more previous line of therapy. Patients with sex cord tumors may be included after prior treatment with a platinum containing regimen (pretreatment with a doxorubicin containing regimen is not required for this patients subgroup).
  • Patient has at least one site of measurable nodal disease at baseline ≥ 2.0 cm in the longest transverse diameter and clearly measurable in at least two perpendicular dimensions, as determined by CT scan (MRI is allowed only if CT scan can not be performed).
  • ECOG performance status (PS) ≤ 2.
  • Adequate haematological, liver and renal function:
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  • Absolute Neutrophil Count (ANC) ≥ 1.5 G/L,
  • Hemoglobin ≥ 9 g/dL,
  • Platelets ≥ 100 G/L,
  • Total calcium (corrected for serum albumin) ≥ lower limit of normal (LLN) or correctable with supplements,
  • Magnesium ≥ LLN or correctable with supplements,
  • Potassium ≥ LLN or correctable with supplements,
  • Phosphorus ≥ LLN or correctable with supplements,
  • Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) (or ≤ 5.0 x ULN if liver metastasis are present),
  • Serum bilirubin ≤ 1.5 x ULN,
  • Serum creatinine ≤ 1.5 x ULN,
  • If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour creatinine clearance must be conducted and the result must be ≥ 50 mL/min.
  • Clinical euthyroidy (patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism).
  • Ability to swallow capsules or tablets.
  • Life expectancy ≥ 12 weeks.
  • Mandatory affiliation with health security insurance.
  • Signed written informed consent.

Who cannot join

  • Prior treatment with any HDAC or HSP90 inhibitor drug.
  • Unresolved toxicities (≥ Grade 1) from prior therapy that would, in the opinion of the investigator, compromise patient safety.
  • Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
  • Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
  • Left ventricular systolic function (LVEF) determined by MUGA scan or echocardiogram < center normal value,
  • Complete left bundle branch block,
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  • Obligate use of a cardiac pacemaker,
  • Congenital long QT syndrome,
  • History or presence of ventricular tachyarrhythmia,
  • Presence of unstable atrial fibrillation (ventricular response > 100bpm),
  • Clinically significant resting bradycardia (< 50 bpm),
  • Mean corrected QT interval (QTcF - n ≥ 3) ≥ 450 msec on screening ECG,
  • Right bundle branch block + left anterior hemiblock (bifasicular block),
  • Angina pectoris ≤ 3 months prior to starting study drug,
  • Acute myocardial infarction (MI) ≤ 3 months prior to starting study drug,
  • History or presence of acute coronary syndrome,
  • Other clinically significant heart disease (e.g.: Congestive heart failure (CHF), uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen),
  • Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LBH589 (e.g.: ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection),
  • Other concurrent severe and/or uncontrolled medical conditions (e.g.: uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease) that could cause unacceptable safety risks or compromise compliance with the protocol.
  • Current treatment with any of the medications listed in appendix 04, if the treatment cannot be discontinued or switched to a different medication prior to starting study drug. The medications listed in appendix 04 have a relative risk of prolonging the QT interval, or inducing Torsades de Pointes, or inhibit CYP3A4/5.
  • Major surgery ≤ 2 weeks prior starting study drug or who have not recovered from side effects of such therapy.
  • History of brain metastases.
  • Absence of at least one metastatic lesion greater than or equal to 2cm on pretreatment CT scan or other radiographic imaging as defined in RECIST criteria (appendix 02).
  • Systemic treatment with any anti-cancer drug, including any investigational drug that is administered on an intermittent schedule if the last dose has not been administered ≥ 4 weeks ago, or if the patient has not recovered from any ongoing toxicity prior to study enrolment.
  • Systemic treatment with any anti-cancer drug, including investigational drug that is administered on a chronic dosing schedule (e.g.: daily dosing, every-other-day dosing, MWF weekly) if ≤ 5 half-lives elapsed since the last dose, or if the patient has not recovered from any ongoing toxicity prior to study enrolment.
  • Women who are pregnant or breast feeding.
  • Women of childbearing potential (WCBP) are excluded unless they have a negative serum pregnancy test ≤ 48 hours prior starting study treatment. All sexually active WCBP and male patients are excluded unless they agree to use adequate contraceptive methods (injectable or implantable hormonal contraceptive, tubal ligation, intra-uterine device, barrier contraceptive with spermacide, or vasectomized partner) throughout the study. Since the potential of LBH589 to induce CYP3A4 is unknown, patients who are using oral contraceptives should use another effective method of contraception.
  • Current immunosuppressive syndrome.
  • History of another malignancy that is currently clinically significant or currently requires active intervention.
  • Refusal or inability to comply with the protocol or follow the instructions given to them by the clinic staff.

Trial locations and contacts

1 site in 1 country.

France1 site

  • Centre Léon Berard

    Lyon

Other trials in France

About this study

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

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.

Read the detailed description

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.

Being tested
LBH589 (Panobinostat®)
Keywords
Sarcoma, Safety, Efficacy, PANOBINOSTAT
Medical subject headings
Sarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LBH589 (Panobinostat®)Drug

    Also called 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.

Study groups in NCT01136499
Study groupRoleWhat they receive
LBH PANOBINOSTATExperimental40 mg 3 days per week
Receives: Drug: LBH589 (Panobinostat®)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 3 months non progression rate

    Measured: 3 months

Secondary outcomes (5)

  1. Progression-free survival (PFS)

    Measured: 6 months after the end of treatment (18 months after the start of treatment)

  2. Time to progression (TTP)

    Measured: 6 months after the end of treatment (18 months after the start of treatment)

  3. best objective response rate

    Measured: 6 months after the end of treatment (18 months after the start of treatment)

  4. Safety profile based on incidence, intensity and type of adverse events

    clinically significant changes in patients physical examination findings; vital sign measuremments; and clinical laboratory results will be recorded and monitored.

    Measured: 6 months after the end of treatment (18 months after the start of treatment)

  5. Plasmatic rate of LBH589

    assess steady-state pharmacokinetics of the new formulation of LBH589 versus that one used in phase one studies.

    Measured: 6 months after the end of treatment (18 months after the start of treatment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jun 2010 (estimated)
  2. Study startJan 2010
  3. Primary completionJan 2012
  4. Study completionJan 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
53 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01136499
Sponsor's protocol ID
ESTIM-LBH
Other IDs
2009-011280-37, 2009
Acronym
ESTIM-LBH
Status last verified
Feb 2013
First submitted
19 Mar 2010
Last updated
6 Mar 2013
Results posted
No
Data monitoring committee
No

Publications

  • Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700-4. doi: 10.1073/pnas.91.21.9700.

    PubMed 7937876

  • Szyf M. DNA methylation properties: consequences for pharmacology. Trends Pharmacol Sci. 1994 Jul;15(7):233-8. doi: 10.1016/0165-6147(94)90317-4.

    PubMed 7940985

  • Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995 Oct 15;55(20):4525-30.

    PubMed 7553621

  • Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995 Jul;1(7):686-92. doi: 10.1038/nm0795-686.

    PubMed 7585152

  • Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 1996 Feb 15;56(4):722-7.

    PubMed 8631003

  • Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870-5. doi: 10.1073/pnas.95.12.6870.

    PubMed 9618505

  • Cameron EE, Baylin SB, Herman JG. p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing. Blood. 1999 Oct 1;94(7):2445-51.

    PubMed 10498617

  • Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol. 1998 Dec;18(12):7185-91. doi: 10.1128/MCB.18.12.7185.

    PubMed 9819405

  • Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 1998 Feb 19;391(6669):815-8. doi: 10.1038/35901.

    PubMed 9486655

  • Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998 Feb 19;391(6669):811-4. doi: 10.1038/35895.

    PubMed 9486654

  • Redner RL, Wang J, Liu JM. Chromatin remodeling and leukemia: new therapeutic paradigms. Blood. 1999 Jul 15;94(2):417-28. No abstract available.

    PubMed 10397708

  • Yoshida M, Nomura S, Beppu T. Effects of trichostatins on differentiation of murine erythroleukemia cells. Cancer Res. 1987 Jul 15;47(14):3688-91.

    PubMed 2439196

  • Yoshida M, Beppu T. Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the G1 and G2 phases by trichostatin A. Exp Cell Res. 1988 Jul;177(1):122-31. doi: 10.1016/0014-4827(88)90030-4.

    PubMed 3134246

  • Itazaki H, Nagashima K, Sugita K, Yoshida H, Kawamura Y, Yasuda Y, Matsumoto K, Ishii K, Uotani N, Nakai H, et al. Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J Antibiot (Tokyo). 1990 Dec;43(12):1524-32. doi: 10.7164/antibiotics.43.1524.

    PubMed 2276972

  • Sugita K, Koizumi K, Yoshida H. Morphological reversion of sis-transformed NIH3T3 cells by trichostatin A. Cancer Res. 1992 Jan 1;52(1):168-72.

    PubMed 1727377

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing LBH589 (Panobinostat®) in people with Soft Tissue Sarcoma, run by Centre Leon Berard at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Mar 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

3 months non progression rate (time frame: 3 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01136499, which also lists 60 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2013.

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