Efficacy of Panobinostat in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma
Condition: Relapsed and Bortezomib Refractory Multiple Myeloma; Refractory Multiple Myeloma; Multiple Myeloma in Relapse
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: panobinostat; bortezomib; dexamethasone
Intervention description: PAN 20 mg PO given TIW, weeks 1&2 of each 3-week cycle;• BTZ 1.3 mg/m2 IV push given BIW weeks 1&2 of each 3 week cycle (days 1,4,8 and 11);• Dex 20 mg PO given QIW, weeks 1&2 of each 3-week cycle (days 1,2,4,5,8,9,11 and 12)
Intervention MeSH terms: Dexamethasone; Bortezomib; Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Multiple Myeloma; Relapsed Multiple Myeloma; Refractory Multiple Myeloma

Summary:

      This study is designed to assess the effectiveness of the combination of Panobinostat plus
      Bortezomib and Dexamethasone in patients with relapsed and bortezomib refractory Multiple
      Myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions.
             All three of the following criteria must have been met:

               -  Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation
                  on serum or on total 24 hour urine

               -  Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma

               -  Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic
                  bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent
                  infections)

          2. Patient must have relapsed and refractory MM and must require treatment for the
             relapsed disease

          3. Patients must have received at least 2 prior lines of therapy which include an IMiD
             (thalidomide or lenalidomide)

          4. Patient must be refractory to the last bortezomib containing line of therapy given in
             the relapsed and refractory setting defined as:

               -  having progressed on or within 60 days of the last bortezomib-containing line of
                  therapy

          5. Patient has measurable disease on M protein at study screening defined by at least one
             of the following measurements as per thresholds clarified in IMWG 2003 disease
             definitions (Kyle, et al 2003):

               -  Serum M-protein ≥ 1 g/dL (≥ 10 g/L)

               -  Urine M-protein ≥ 200 mg/24 h

          6. Patients treated with local radiotherapy with or without concomitant exposure to
             steroids for pain control or management of cord/nerve root compression, are eligible.
             Two weeks must have lapsed since last date of radiotherapy, which is recommended to be
             a limited field. Patients who require concurrent radiotherapy should have entry to the
             protocol deferred until the radiotherapy is completed and 2 weeks have passed since
             the last date of therapy

          7. Patient's age is ≥ 18 years at time of signing the informed consent

          8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤
             2

          9. Patient has the following laboratory values within 3 weeks before starting study drug
             (lab tests may be repeated, as clinically indicated, to obtain acceptable values
             before screen fail is concluded but supportive therapies are not to be administered
             within the week prior to screening tests for absolute neutrophil count or platelet
             counts)

               -  Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L

               -  Platelet count ≥ 70 x 109 /L

               -  Serum potassium, magnesium, phosphorus, within normal limits (WNL) for
                  institution

               -  Total calcium (corrected for serum albumin) or ionized calcium ≥ LLN, and not
                  higher than CTCAE grade 1 in case of elevated value

             Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to
             correct values that are < LLN:

               -  AST/SGOT and ALT/SGPT ≤ 2.5 x ULN

               -  Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome)

               -  Serum creatinine levels ≤ 2.5 x ULN, or calculated creatinine clearance ≥ 40
                  ml/min

         10. Patient has provided written informed consent prior to any screening procedures

         11. Patient is able to swallow capsules

         12. Patient must be able to adhere to the study visit schedule and other protocol
             requirements

         13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at
             within 7 days prior to start of study treatment

        Exclusion Criteria:

          1. Primary refractory disease (patients that never reached at least an MR for over 60
             days under any prior therapy)

          2. Patients who have a history of prior MM treatment with a DAC inhibitor including
             panobinostat

          3. Patients who have had prior allogeneic stem cell transplantation and show evidence of
             active graft-versus-host disease that requires immunosuppressive therapy

          4. Peripheral neuropathy ≥ CTCAE grade 2

          5. Patients who will need valproic acid for any medical condition during the study or
             within 5 days prior to the first administration of study drug / treatment or who
             cannot be switch to safely to alternative anti-epileptic medication

          6. Patients who have impaired cardiac function including any of the following:

               -  Congenital long QT syndrome, complete left bundle branch block or use of a
                  permanent cardiac pacemaker, history or presence of ventricular tachyarrhythmias,
                  clinically significant resting bradycardia (< 50 beats per minute). Right bundle
                  branch block + left anterior hemiblock (bifascicular block)

               -  QTcF > 450 msec on screening ECG

               -  Presence of unstable atrial fibrillation. Patients with stable atrial
                  fibrillation are allowed in the study provided they do not meet other cardiac or
                  prohibited drug exclusion criteria

               -  Previous history of angina pectoris or acute MI within 6 months

               -  Congestive heart failure (New York Heart Association functional classification
                  III-IV)

               -  Patient has any other clinically significant cardiovascular disease (e.g.
                  uncontrolled hypertension)

          7. Patient has an impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of panobinostat (e.g., ulcerative disease,
             uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or significant
             small bowel resection)

          8. Patient has unresolved diarrhea ≥ CTCAE grade 2

          9. Patients who have any other concurrent severe and/or uncontrolled medical condition(s)
             including, but not limited to: uncontrolled diabetes mellitus, active or uncontrolled
             infection, chronic obstructive or chronic restrictive pulmonary disease (e.g. dyspnea
             at rest from any cause), symptomatic thyroid dysfunction, significant bleeding
             tendency, that could cause unacceptable safety risks or compromise compliance with the
             protocol

         10. Patients who are using medications that have a known relative risk of prolonging the
             QT interval or of inducing Torsade de Pointes, where such treatment cannot be
             discontinued or switched to a different medication prior to starting study drug

         11. Women who are pregnant or breast feeding

         12. Patients with evidence of another malignancy not in remission or history of such a
             malignancy within the last 5 years (except for treated basal or squamous cell
             carcinoma, or in situ cancer of the cervix)

         13. Patients who have received prior to starting study treatment either radiation therapy
             to > 30% of marrow-bearing bone within 4 weeks; myelotoxic chemotherapy within 4
             weeks; or immunotherapy within 8 weeks; or who have not yet recovered from side
             effects of such therapies

         14. 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

         15. Use of chemo-, biologic or immunologic therapy and/or other investigational agents
             while the patient is on study treatment.

         16. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted
             only if commenced prior to the start of screening period)