Clinical trial NCT00445068: Efficacy and Safety of LBH589B in Adult Patients With Multiple Myeloma
Official title: A Phase II Study Of Oral LBH589 In Adult Patients With Multiple Myeloma Who Have Received At Least Two Prior Lines Of Therapy And Whose Disease Is Refractory To The Most Recent Line Of Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple myeloma
adults
LBH589
refractory
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2007-03-08
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will evaluate the efficacy and safety of LBH589B in adult patients with multiple myeloma who have received at least two prior therapies and are refractory to their last therapy. Patients must have received in prior therapy either bortezomib or lenalidomide


Eligibility criteria: Inclusion criteria:

1. Adults ≥ 18 years old
2. Subjects must have signed the consent form before undergoing any study specific screening procedures and before participation in this study. The subject must be fully informed by the investigator of the nature and potential risks of participation in this study.
3. Patients must have had a diagnosis of symptomatic multiple myeloma (from IMWG see (Kyle et al,2003) meeting all three of the following criteria:

   * Monoclonal immunoglobulin (spike on electrophoresis, or band on immunofixation) on serum or on 24 hour urine.
   * Bone marrow (clonal) plasma cells or plasmacytoma
   * Related organ or tissue impairment (anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity or recurrent infections) (The Kyle et al 2003 definition of symptomatic Myeloma has been adapted based on the new exclusion criteria defined in protocol amendment 1)
4. Subjects must have received at least two prior lines of therapy and be refractory to the most recent line of therapy according to the following definitions: Refractory to most recent line of therapy Defined by disease progression during treatment or within 60 - 100 days after the completion of the most recent line of therapy. This includes the development of disease progression during maintenance or consolidation therapy with high dose glucocorticoids, or any other specific MM therapy Sixty days is counted from the point in time when the first response assessment is performed after completion of the last line of therapy. At a maximum, disease progression should be documented within 100 days after the last day of the last dose of any anti-MM therapy, including if last regimen of the most recent line of therapy was Autologous Stem Cell Transplant (ASCT). Stable disease patients also part of the IMWG definition are not eligible for this trial. At study screening, Progressive Disease (PD) will be assessed by comparing screening values or symptoms in reference to the baseline (values or symptoms) of their last line of therapy. Should a patient have experienced an initial response on their last line of therapy, PD should be assessed in reference to the lowest values of the initial confirmed response Minimal Response(MR) / Partial Response (PR) / Complete Response (CR).

   Disease progression is defined by having one or more of the following:
   * \>25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation.
   * \>25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200 mg/24 h and confirmed on a repeat investigation.
   * \>25% increase in plasma cells in a bone marrow aspirate or on bone marrow biopsy, which must also be an absolute increase of at least 10%
   * Definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas.
   * Development of new bone lesions or soft tissue plasmacytomas (not including compression fracture).
   * Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.8 mmol/L not attributable to any other cause).
5. Subjects must have previously been treated with bortezomib and at least one of the following: lenalidomide or thalidomide
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
7. Patients must have the following hematological laboratory values:

   * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (or ≥1.0 x 109/L if the neutropenia is clinically related to progressive myeloma with bone marrow infiltration of \> 50% involvement
   * Hemoglobin ≥ 8.0 g/dl
   * Platelets ≥ 75.0 x 109/L (or ≥ 50.0 x 109/L x if the thrombocytopenia is clinically related to progressive myeloma with bone marrow infiltration \> 50% involvement
8. Patients must have the following renal function as shown by :

   * Calculated Creatinine Clearance (CrCL) \> 30ml/min (Cockcroft and Gault formula)
9. Patients must have adequate liver function as shown by:

   * Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x Upper limit of normal (ULN)
   * Serum bilirubin ≤ 1.5 x ULN
   * Albumin ≥ 2.5 g/dl
10. Patients must have the following non-hematological laboratory values:

    * Serum potassium ≥ Lower Limit of Normal (LLN),
    * Total serum calcium \[corrected for serum albumin\] or ionized calcium ≥LLN,
    * Serum magnesium ≥ LLN
    * Serum phosphorus ≥ LLN
    * Normal thyroid function (TSH and free T4) (hypothyroidism correctable with supplements is allowed)
11. Baseline Multiple Uptake Gated Acquisition scan (MUGA) or echocardiogram (ECHO) must demonstrate Left Ventricular Ejection Fraction (LVEF) ≥ the lower limit of the institutional normal
12. Patients must be willing and able to undergo bone marrow aspirates as per protocol, with/without bone marrow biopsy according to their center's practice. The bone marrow aspirate /biopsy must be adequate to allow for comparison for the later efficacy response assessments.
13. Patients must have an M component at baseline above a minimum threshold of: 1g/dl (10g/L) for serum M component, or 200mg/24h urine M component.

Exclusion criteria:

1. Prior therapy with an Histone Deacetylase (HDAC) inhibitor for the treatment of Multiple Myeloma (MM)
2. Patients with non-secretory MM
3. Patients who have received allogenic stem cell transplantation \< 12 months prior to study
4. Patients who have had prior allogenic stem cell transplantation and show evidence of active graft versus-host disease that requires immunosuppressive therapy
5. Patients with amyloidosis
6. Patients with peripheral neuropathy \> grade 2
7. 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 Heart Rate (HR)\< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.
   * Screening Electrocardiogram (ECG) with a corrected QT interval (QTc) \> 450 msec
   * Right bundle branch block + left anterior hemi-block (bi-fascicular block)
   * Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug
8. Other clinically significant heart disease (e.g., Congestive Heart Failure (CHF NY) Heart Association class III or IV, uncontrolled hypertension, or history of poor compliance with an antihypertensive regimen)
9. Impairment of GI function or GI disease that may significantly alter the absorption of LBH589
10. Patients with unresolved diarrhea \> CTCAE grade 1.
11. Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol
12. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsades de pointes if the medications cannot be discontinued or switched to a different medication prior to starting study drug
13. Concomitant use of CYP3A4 inhibitors
14. Patients with an active bleeding diathesis or on any treatment with therapeutic doses of sodium warfarin (Coumadin®) or any other anti-vitamin K drug. Low doses of Coumadin® (e.g., ≤ 2 mg/day), or low doses of any other anti-vitamin K drug, for line patency is allowable
15. Patients who have received chemotherapy, radiation therapy or any investigational drugs, bortezomib or other immunomodulatory therapy (e.g., thalidomide, lenalidomide) or immunotherapy ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such therapy
16. Patients who have received high-dose corticosteroids as the only component of their most recent line of therapy
17. Patients who have received steroids (e.g., dexamethasone) ≤ 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 subjects receive \< 20 mg of prednisone or equivalent as indicated for other medical conditions (and not as maintenance or an anticancer therapy for MM), or up to 100 mg of hydrocortisone as premedication for a administration of certain medications or blood products, while enrolled in this study.
18. Patients whose clinical condition would need valproic acid therapy during study or ≤ 5 days prior to starting drug
19. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
20. 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 LBH589
21. 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
22. Patients with a current second malignancy or a prior malignancy within the last 5 years except adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
23. Patients with any significant history of non compliance to medical regimens or unwilling or unable to comply with the protocol or unable to grant reliable informed consent.

Primary outcomes:
measure: Response Rate (Complete Response(CR) / Partial Response (PR))
timeFrame: From Start of the Study up to 57 Weeks approximately.
Secondary outcomes:
measure: Overall Response Rate
timeFrame: From Start of the Study up to 57 Weeks approximately.
measure: Clinical Benefit Rate
timeFrame: From Start of the Study up to 57 Weeks approximately.
measure: Duration of Response
timeFrame: From Start of the Study up to 57 Weeks approximately.
measure: Time to Response
timeFrame: From Start of the Study up to 57 Weeks approximately.
measure: Progression Free Survival (PFS)
timeFrame: From Start of the Study up to 57 Weeks approximately.
measure: Safety and Tolerability
timeFrame: From Start of the Study up to 57 Weeks approximately.
measure: Time to Peak Concentration (Tmax) of Panobinostat
timeFrame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
measure: Maximum Plasma Concentration (Cmax) of Panobinostat
timeFrame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
measure: Area Under the Plasma Concentration (AUC0-24) of Panobinostat
timeFrame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
measure: Last Observed Plasma Concentration (Clast) of Panobinostat
timeFrame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
measure: Time of Clast (Tlast) of Panobinostat
timeFrame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Berkeley
country: United States
facility: Aptium Oncology
state: California
city: Duarte
country: United States
facility: City of Hope
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Stanford
country: United States
facility: Stanford
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Newark
country: United States
facility: Christiana Care
state: Delaware
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Dana Farber
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University
state: New Jersey
city: Durham
country: United States
facility: Duke
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest
state: North Carolina
city: Cleveland
country: United States
facility: Metrohealth
state: Ohio
city: Nashville
country: United States
facility: Sarah Canon Research Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: San Antonio
country: United States
facility: CTRC
state: Texas
city: Berlin
country: Germany
facility: Novartis investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Starnberg
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: