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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Relapsed and Bortezomib Refractory Multiple Myeloma, Refractory Multiple Myeloma, Multiple Myeloma in Relapse

Intervention / Treatment
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* Drug: panobinostat
* Drug: bortezomib
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Patient must have relapsed and refractory MM and must require treatment for the relapsed disease Patients must have received at least 2 prior lines of therapy which include an IMiD (thalidomide or lenalidomide) 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 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 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 Patient's age is ≥ 18 years at time of signing the informed consent Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2 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 Patient has provided written informed consent prior to any screening procedures Patient is able to swallow capsules Patient must be able to adhere to the study visit schedule and other protocol requirements Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at within 7 days prior to start of study treatment Exclusion Criteria: Primary refractory disease (patients that never reached at least an MR for over 60 days under any prior therapy) Patients who have a history of prior MM treatment with a DAC inhibitor including panobinostat Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy Peripheral neuropathy ≥ CTCAE grade 2 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 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) 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) Patient has unresolved diarrhea ≥ CTCAE grade 2 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 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 Women who are pregnant or breast feeding 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) 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 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 Use of chemo-, biologic or immunologic therapy and/or other investigational agents while the patient is on study treatment. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: panobinostat + bortezomib & dexamethasone<br>panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma | Drug: panobinostat<br>* 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)<br>* Other names: PAN;Drug: bortezomib<br> <br> * Other names: BTZ;Drug: dexamethasone<br> <br> * Other names: DEX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (PR+nCR+CR) | Overall response rate=(PR+nCR+CR) CR= < 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks. | after eight cycyles of treatment (24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responders to Treatment | The primary endpoint for this phase II study of patients with bortezomib-refractory MM is response after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria. | after eight cycyles of treatment (24 weeks) | 
| Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment | Time to response is defined as the time from the date of first administration of study treatment to the date of first documented evidence of CR or nCR or PR (whichever status is recorded first). Patients who do not have a response of PR or better by the data cut-off date are censored. | after eight cycyles of treatment (24 weeks) | 
| Progression-free Survival | Progression-free survival (PFS) was defined as the time from the date of first study treatment to first occurrence of documented progressive disease /relapse or death. Time from randomization until disease progression or death by Kaplan-Meier estimates | 24 weeks | 
| Time to Progression | Time from randomization until objective tumor progression; does not include deaths-- Kaplan-Meier estimates | 24 weeks | 
| Over All Survival | Kaplan Meier estimates- median time to event | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Relapsed Multiple Myeloma, Refractory Multiple Myeloma