Efficacy of Panobinostat in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma

A Phase II, Multi-center, Single Arm, Open Label Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma

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.

This is a phase II, two stage, single arm, open label, multi-center study of oral PAN in combination with BTZ/Dex in patients with relapsed and refractory multiple myeloma, who are bortezomib-refractory and have received at least 2 prior lines of therapy. Patients must have been exposed to an iMID (lenalidomide or thalidomide) and progressed on or within 60 days of their last BTZ-containing line of therapy.

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)