Clinical trial NCT00532389 (phase 1, status: completed)
Conditions: multiple myeloma
ICD codes: C90.01, C90.02, C90.00
Drugs: lbh589
SMILES: [H]\C(=C(\[H])C1=CC=C(CNCCC2=C(C)NC3=CC=CC=C23)C=C1)C(O)=NO
Eligibility criteria:

        Inclusion criteria:

          1. Patients must have a diagnosis of active multiple myeloma according to the
             International Myeloma Working Group criteria (IMWG., 2003), and be deemed by the
             investigator as requiring treatment.

          2. Patients must have received at least one prior line of therapy and includes patients
             whose disease has relapsed as well as relapsed-refractory MM . (Durie et. al., 2006).
             One prior line of therapy may consist of induction followed by autologous stem cell
             transplantation.

          3. Patients must be suitable (according to their local product information and applicable
             health authority recommendations) for treatment with BTZ. Note: patients previously
             treated with BTZ are eligible to participate in the trial.

          4. Patients enrolled to dose expansion phase must have measurable M component at entry
             according to the IMWG Criteria (Durie et al, 2006) including at least one of the
             following:

               -  Serum M-protein by sPEP ≥ 1 g/dL (> 10g/l)

               -  For patients with IgA M-protein whose sPEP is not providing sufficiently precise
                  quantification due to confounded migration of M-protein with serum beta
                  globulins, a quantification by nephelometry / turbidometry is permitted and must
                  show serum M-protein ≥ 1 g/dL

               -  Urine M-protein by uPEP ≥ 200 mg/24 h

               -  Serum FLC assay: Involved FLC level ≥ 100 mg/L, provided serum FLC ratio is
                  abnormal. (abnormal if FLC ratio is <0.26 or >1.65 )

          5. Adults ≥ 18 years old

          6. ECOG Performance Status ≤ 2

          7. Life expectancy > 12 weeks

          8. Patients must have the following laboratory values:

               -  ANC ≥ 1.5 x 109/L

               -  Platelets ≥ 100x 109/L

               -  Calculated CrCl ≥ 30 mL/min (MDRD Formula)

               -  AST and ALT ≤ 2.5 x ULN

               -  Serum bilirubin ≤ 1.5 x ULN

               -  Serum potassium, magnesium, phosphorous, within normal limits (WNL) for
                  institution

               -  Total calcium (corrected for serum albumin) or ionized calcium equal to lower
                  normal limits for institution or greater (≥ LLN) but not higher than CTCAE grade
                  1

               -  Note: Potassium, calcium, magnesium, and/or phosphorous supplements may be given
                  to correct values that are < LLN.

          9. Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional
             normal

         10. All patients (dose-escalation and dose-expansion patients) must be willing to undergo
             a mandatory bone marrow aspirate sampling at baseline (for cytology) and another later
             in the study if the patient eventually goes on to experience a CR or PR. For patients
             who join the study at the dose-expansion phase, they must also give consent to have an
             extra volume of sample taken for exploratory biomarker testing. Potential
             dose-expansion phase patients who do not consent for this biomarker sample collection
             will not be eligible to participate in the trial (Note: One extra bone aspirate sample
             at C2D1 is optional as per the protocol).

         11. Able to sign informed consent and to comply with the protocol

         12. Patient is able to swallow capsules

        Exclusion criteria:

          1. Prior exposure to a HDAC inhibitor compound used in the treatment of MM

          2. Patients with Refractory MM (i.e. patients refractory to all prior therapies) who
             under all prior previous lines of therapy have :

               -  either never reached a response better than SD

               -  or whose disease progressed from any best response while still under therapy

               -  or whose disease progressed within 60 days of last dose of therapy

          3. Patients who have had prior allogeneic stem cell transplantation and show evidence of
             active graft-versus-host disease or of graft-versus-host disease that requires
             immunosuppressive therapy.

          4. Patient has grade 1 peripheral neuropathy with pain or grade ≥ 2 peripheral neuropathy
             on clinical examination within 14 days before first study treatment

          5. Impaired cardiac function or clinically significant cardiac diseases, including any
             one of the following:

               -  Patients with congenital long QT syndrome

               -  History or presence of sustained ventricular tachyarrhythmia. (Patients with a
                  history of atrial arrhythmia are eligible but should be discussed with the
                  Sponsor prior to enrollment)

               -  Any history of ventricular fibrillation or torsade de pointes

               -  Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥
                  50 bpm.

               -  Screening ECG with a QTc > 450 msec

               -  Right bundle branch block + left anterior hemiblock (bifascicular block)

               -  Patients with myocardial infarction or unstable angina ≤ 6 months prior to
                  starting study drug

               -  Other clinically significant heart disease (e.g., CHF NY Heart Association class
                  III or IV , uncontrolled hypertension, history of labile hypertension, or history
                  of poor compliance with an antihypertensive regimen)

          6. Impairment of GI function or GI disease that may significantly alter the absorption of
             PAN

          7. Patient has unresolved diarrhea ≥ CTCAE grade 2

          8. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
             diabetes, active or uncontrolled infection, acute diffuse pulmonary disease,
             pericardial disease, uncontrolled thyroid dysfunction ) including abnormal laboratory
             values, that could cause unacceptable safety risks or compromise compliance with the
             protocol

          9. Patients using medications that have a relative risk of prolonging the QT interval or
             inducing torsade de pointes if treatment cannot be discontinued or switched to a
             different medication prior to starting study drug

         10. Patients who need valproic acid for any medical condition during the study or within 5
             days prior to the first PAN treatment.

         11. Patients who have received targeted agents within 2 weeks or within 5 half-lives of
             the agent and active metabolites (which ever is longer) and who have not recovered
             from side effects of those therapies.

         12. Patients who have received either immunotherapy within ≤ 8 weeks; chemotherapy within
             ≤ 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within ≤ 2 weeks prior
             to starting study treatment; or who have not yet recovered from side effects of such
             therapies.

         13. Patients who have received steroids (e.g. Dex) ≤ 2 weeks prior to starting study
             treatment or who have not recovered from side effects of such therapy. Concomitant
             therapy medications that include corticosteroids are allowed if patients receive < 10
             mg of prednisone or equivalent as indicated for other medical conditions, or up to 100
             mg of hydrocortisone as pre-medication for administration of certain medications or
             blood products while enrolled in this study.

         14. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
             who have not recovered from side effects of such therapy

         15. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)not
             willing to use a double method of contraception during the study and for 3 months
             after treatment. One of these methods of contraception must be a barrier method. WOCBP
             are defined as women who have not undergone a hysterectomy or who have not been
             naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses
             any time in the preceding 12 consecutive months). Women of childbearing potential must
             have a negative serum pregnancy test within 7 days of the first administration of oral
             PAN

         16. Male patients whose sexual partners are WOCBP not using a double method of
             contraception during the study and for 3 months after treatment. One of these methods
             of contraception must be a condom

         17. Patients with a prior malignancy with in the last 3 years (except for basal or
             squamous cell carcinoma, or in situ cancer of the cervix)

         18. Patients with any significant history of non-compliance to medical regimens or
             unwilling or unable to comply with the instructions given to him/her by the study
             staff.

         19. Patients who have shown intolerance to BTZ or to Dex or components of these drugs or
             has any contraindication to one or the other drug, following locally applicable
             prescribing information

        Other protocol defined inclusion/exclusion criteria may apply