Clinical trial NCT01136499 (phase 2, status: completed)
Conditions: soft tissue sarcoma
ICD codes: C46.1
Drugs: lbh589 (panobinostat®)
SMILES: [H]\C(=C(\[H])C1=CC=C(CNCCC2=C(C)NC3=CC=CC=C23)C=C1)C(O)=NO
Eligibility criteria:

        INCLUSION CRITERIA

          -  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:

               -  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.

        EXCLUSION CRITERIA

          -  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,

                    -  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.