Efficacy and Safety of LBH589B in Adult Patients With Multiple Myeloma

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00445068
• Collaborator: (none)
• Enrollment: 38
• Locations: 29
• Arm: 1
• Actual Duration (Months): 32.3
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: LBH589	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 16, 2007
• Actual Primary Completion Date: May 19, 2008
• Actual Study Completion Date: Dec 25, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panobinostat Participants received panobinostat 20 milligrams (mg) orally once daily (OD), three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.	Drug: LBH589; Other Names: Panobinostat

Outcome Measures

Primary Outcome Measures

1. Response Rate (Complete Response(CR) / Partial Response (PR)) [From Start of the Study up to 57 Weeks approximately.]

   The response (complete response (CR) / partial response (PR)) rate as per Bladé criteria was assessed by the investigator. Response to treatment was evaluated in participants with multiple myeloma (MM) who have received at least two prior lines of therapy and whose disease was refractory to the most recent line of therapy.

Secondary Outcome Measures

1. Overall Response Rate [From Start of the Study up to 57 Weeks approximately.]

   Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

2. Clinical Benefit Rate [From Start of the Study up to 57 Weeks approximately.]

   Clinical benefit rate is defined by the percentage of participants achieving either a confirmed tumor response or stable disease (SD) for at least 24 weeks. Response Criteria in Solid Tumors (RECIST) is a system for measuring tumor shrinkage or progression in terms of the longest dimensions of the tumor on imaging scans such as computerized tomography (CT). A "partial response" requires a decrease of 30% or more, "Progression" requires an increase of at least 20%, and "Stable disease" falls in between these two. All responses have a repeat assessment to confirm the response

3. Duration of Response [From Start of the Study up to 57 Weeks approximately.]

   Duration of response is defined as time between time to first documented response (CR/PR) and time to first documented disease progression or death.

4. Time to Response [From Start of the Study up to 57 Weeks approximately.]

   Time to response is defined as time between Day 1 cycle 1 and time to first documented response (CR/PR).

5. Progression Free Survival (PFS) [From Start of the Study up to 57 Weeks approximately.]

   Progressions free survival is defined as time between Day 1 cycle 1 and time to first documented disease progression or death. Disease progression will be determined as per response criteria.

6. Safety and Tolerability [From Start of the Study up to 57 Weeks approximately.]

   Adverse Event (AE) are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

7. Time to Peak Concentration (Tmax) of Panobinostat [Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8]

   Tmax is defined as the time at which the Cmax occurs. It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject's pharmacokinetic (PK) profile, then Tmax will be missing for that subject. Tmax will be reported in units of h.

8. Maximum Plasma Concentration (Cmax) of Panobinostat [Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8]

   Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Cmax will be missing for that subject. Cmax will be reported in units of ng/mL.

9. Area Under the Plasma Concentration (AUC0-24) of Panobinostat [Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8]

   Area under the curve (AUC) is defined as the area under concentration-time curve as a measure of drug exposure. The area under the plasma concentration-time curve from time zero to 24 hours.

10. Last Observed Plasma Concentration (Clast) of Panobinostat [Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8]

    Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast.

11. Time of Clast (Tlast) of Panobinostat [Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8]

    Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Tlast will be missing for that participants. Tlast will be reported in units of h.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

1. 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).

1. Subjects must have previously been treated with bortezomib and at least one of the following: lenalidomide or thalidomide

2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2

3. 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

1. Patients must have the following renal function as shown by :

• Calculated Creatinine Clearance (CrCL) > 30ml/min (Cockcroft and Gault formula)

1. 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

1. 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)

1. Baseline Multiple Uptake Gated Acquisition scan (MUGA) or echocardiogram (ECHO) must demonstrate Left Ventricular Ejection Fraction (LVEF) ≥ the lower limit of the institutional normal

2. 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.

3. 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

1. 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)

2. Impairment of GI function or GI disease that may significantly alter the absorption of LBH589

3. Patients with unresolved diarrhea > CTCAE grade 1.

4. Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol

5. 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

6. Concomitant use of CYP3A4 inhibitors

7. 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

8. 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

9. Patients who have received high-dose corticosteroids as the only component of their most recent line of therapy

10. 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.

11. Patients whose clinical condition would need valproic acid therapy during study or ≤ 5 days prior to starting drug

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

13. 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

14. 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

15. 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

16. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85259
2	Aptium Oncology	Berkeley	California	United States	94704
3	City of Hope	Duarte	California	United States	91010
4	UCSF	San Francisco	California	United States	94143
5	Stanford	Stanford	California	United States	94305
6	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
7	Christiana Care	Newark	Delaware	United States	19718
8	Moffitt Cancer Center	Tampa	Florida	United States	33612
9	Emory University	Atlanta	Georgia	United States	30322
10	Rush University	Chicago	Illinois	United States	60612
11	University of Chicago	Chicago	Illinois	United States	60637
12	Indiana University	Indianapolis	Indiana	United States	46203
13	University of Iowa	Iowa City	Iowa	United States	52240-1515
14	Dana Farber	Boston	Massachusetts	United States	02115
15	University of Michigan	Ann Arbor	Michigan	United States	48109
16	Washington University	Saint Louis	Missouri	United States	63110
17	Hackensack University	Hackensack	New Jersey	United States	07456
18	Duke	Durham	North Carolina	United States	27710
19	Wake Forest	Winston-Salem	North Carolina	United States	27157
20	Metrohealth	Cleveland	Ohio	United States	44109
21	Sarah Canon Research Center	Nashville	Tennessee	United States	37203
22	Vanderbilt	Nashville	Tennessee	United States	37212
23	University of Texas Southwestern	Dallas	Texas	United States	75390-9179
24	CTRC	San Antonio	Texas	United States	78258
25	Novartis investigative Site	Berlin		Germany
26	Novartis Investigative Site	Heidelberg		Germany
27	Novartis Investigative Site	Kiel		Germany
28	Novartis Investigative Site	Starnberg		Germany
29	Novartis Investigative Site	Wuerzburg		Germany

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00445068
• Other Study ID Numbers: CLBH589B2203
• First Posted: Mar 8, 2007
• Last Update Posted: Jul 14, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Novartis Pharmaceuticals: Multiple myeloma; adults; LBH589; refractory
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Panobinostat

Study Results

Participant Flow

Recruitment Details	The study was conducted at 27 centers in 6 countries
Pre-assignment Detail	A total 38 participants were enrolled in the study, of which 38 discontinued the study.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 milligrams (mg) orally once daily (OD), three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	38
COMPLETED	2
NOT COMPLETED	36

Baseline Characteristics

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle.
Overall Participants	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (6.58)
Sex: Female, Male (Count of Participants)
Female	14 36.8%
Male	24 63.2%
Race/Ethnicity, Customized (Count of Participants)
Black	5 13.2%
Caucasian	31 81.6%
Other	1 2.6%
Pacific islander	1 2.6%

Outcome Measures

1. Primary Outcome

Title	Response Rate (Complete Response(CR) / Partial Response (PR))
Description	The response (complete response (CR) / partial response (PR)) rate as per Bladé criteria was assessed by the investigator. Response to treatment was evaluated in participants with multiple myeloma (MM) who have received at least two prior lines of therapy and whose disease was refractory to the most recent line of therapy.
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed in Full Analysis Set (FAS) population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	0

2. Secondary Outcome

Title	Overall Response Rate
Description	Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	0

3. Secondary Outcome

Title	Clinical Benefit Rate
Description	Clinical benefit rate is defined by the percentage of participants achieving either a confirmed tumor response or stable disease (SD) for at least 24 weeks. Response Criteria in Solid Tumors (RECIST) is a system for measuring tumor shrinkage or progression in terms of the longest dimensions of the tumor on imaging scans such as computerized tomography (CT). A "partial response" requires a decrease of 30% or more, "Progression" requires an increase of at least 20%, and "Stable disease" falls in between these two. All responses have a repeat assessment to confirm the response
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	0

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined as time between time to first documented response (CR/PR) and time to first documented disease progression or death.
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	0

5. Secondary Outcome

Title	Time to Response
Description	Time to response is defined as time between Day 1 cycle 1 and time to first documented response (CR/PR).
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	0

6. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progressions free survival is defined as time between Day 1 cycle 1 and time to first documented disease progression or death. Disease progression will be determined as per response criteria.
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	0

7. Secondary Outcome

Title	Safety and Tolerability
Description	Adverse Event (AE) are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time Frame	From Start of the Study up to 57 Weeks approximately.

Outcome Measure Data

Analysis Population Description

The analysis was performed on Safety population consisted of all participants who had received at least one dose of study medication and had one valid post-baseline assessment.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	38
Participants with Adverse Events	38 100%
Deaths	7 18.4%
On treatment deaths	3 7.9%
Serious Adverse Events	17 44.7%
Study-drug-related Serious Adverse Events	3 7.9%
Adverse Events Leading to discontinuation	8 21.1%

8. Secondary Outcome

Title	Time to Peak Concentration (Tmax) of Panobinostat
Description	Tmax is defined as the time at which the Cmax occurs. It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject's pharmacokinetic (PK) profile, then Tmax will be missing for that subject. Tmax will be reported in units of h.
Time Frame	Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The analysis was performed in Pharmacokinetic Analysis (PAS) population, defined as all participants who provide at least one post-dose Pharmacokinetic (PK) plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	27
Day 1	1.7
Day 8	1.2

9. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Panobinostat
Description	Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Cmax will be missing for that subject. Cmax will be reported in units of ng/mL.
Time Frame	Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	27
Day 1	7.6 (5.52)
Day 8	9.7 (6.51)

10. Secondary Outcome

Title	Area Under the Plasma Concentration (AUC0-24) of Panobinostat
Description	Area under the curve (AUC) is defined as the area under concentration-time curve as a measure of drug exposure. The area under the plasma concentration-time curve from time zero to 24 hours.
Time Frame	Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	27
Day 1	72.0 (36.10)
Day 8	81.6 (37.56)

11. Secondary Outcome

Title	Last Observed Plasma Concentration (Clast) of Panobinostat
Description	Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast.
Time Frame	Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	27
Day 1	0.3 (0.18)
Day 8	1.1 (1.13)

12. Secondary Outcome

Title	Time of Clast (Tlast) of Panobinostat
Description	Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Tlast will be missing for that participants. Tlast will be reported in units of h.
Time Frame	Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. Participants could continue treatment until disease progression or unacceptable toxicity.
Measure Participants	27
Day 1	47.8
Day 8	24.3

Adverse Events

Time Frame	From Start of the Study up to 57 Weeks approximately.
Adverse Event Reporting Description	The analysis was performed on safety set population defined as all participants who received study drug and had at least one post-baseline safety assessment.
Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle.
All Cause Mortality
	Panobinostat
	Affected / at Risk (%)	# Events
Total	7/38 (18.4%)
Serious Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	17/38 (44.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/38 (2.6%)
Thrombocytopenia	3/38 (7.9%)
Gastrointestinal disorders
Diarrhoea	2/38 (5.3%)
Dysphagia	1/38 (2.6%)
Nausea	2/38 (5.3%)
Retching	1/38 (2.6%)
Vomiting	2/38 (5.3%)
General disorders
General physical health deterioration	1/38 (2.6%)
Pain	1/38 (2.6%)
Pyrexia	2/38 (5.3%)
Infections and infestations
Gastroenteritis	1/38 (2.6%)
Infection	1/38 (2.6%)
Pneumonia	4/38 (10.5%)
Respiratory tract infection	1/38 (2.6%)
Sepsis syndrome	1/38 (2.6%)
Streptococcal infection	1/38 (2.6%)
Upper respiratory tract infection	1/38 (2.6%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/38 (2.6%)
Hip fracture	1/38 (2.6%)
Multiple fractures	1/38 (2.6%)
Investigations
Blood creatinine increased	1/38 (2.6%)
Monoclonal immunoglobulin present	1/38 (2.6%)
Metabolism and nutrition disorders
Dehydration	2/38 (5.3%)
Hypercalcaemia	4/38 (10.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/38 (2.6%)
Back pain	1/38 (2.6%)
Haemarthrosis	1/38 (2.6%)
Neck pain	1/38 (2.6%)
Spinal column stenosis	1/38 (2.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone	1/38 (2.6%)
Nervous system disorders
Cerebrovascular accident	1/38 (2.6%)
Somnolence	1/38 (2.6%)
Uraemic encephalopathy	1/38 (2.6%)
Psychiatric disorders
Anxiety	1/38 (2.6%)
Emotional distress	1/38 (2.6%)
Renal and urinary disorders
Renal failure	1/38 (2.6%)
Renal failure acute	1/38 (2.6%)
Other (Not Including Serious) Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	37/38 (97.4%)
Blood and lymphatic system disorders
Anaemia	13/38 (34.2%)
Leukopenia	2/38 (5.3%)
Neutropenia	13/38 (34.2%)
Thrombocytopenia	16/38 (42.1%)
Gastrointestinal disorders
Abdominal pain upper	4/38 (10.5%)
Constipation	5/38 (13.2%)
Diarrhoea	16/38 (42.1%)
Nausea	20/38 (52.6%)
Vomiting	12/38 (31.6%)
General disorders
Asthenia	2/38 (5.3%)
Fatigue	18/38 (47.4%)
Gait disturbance	2/38 (5.3%)
Oedema peripheral	8/38 (21.1%)
Pain	2/38 (5.3%)
Pyrexia	8/38 (21.1%)
Infections and infestations
Gastrointestinal infection	2/38 (5.3%)
Influenza	2/38 (5.3%)
Nasopharyngitis	3/38 (7.9%)
Pneumonia	2/38 (5.3%)
Upper respiratory tract infection	3/38 (7.9%)
Urinary tract infection	3/38 (7.9%)
Investigations
Blood creatinine increased	10/38 (26.3%)
Blood uric acid increased	2/38 (5.3%)
Electrocardiogram QT prolonged	2/38 (5.3%)
Weight decreased	4/38 (10.5%)
Metabolism and nutrition disorders
Decreased appetite	7/38 (18.4%)
Hypercalcaemia	3/38 (7.9%)
Hyperkalaemia	2/38 (5.3%)
Hypokalaemia	6/38 (15.8%)
Hypomagnesaemia	4/38 (10.5%)
Hypophosphataemia	3/38 (7.9%)
Musculoskeletal and connective tissue disorders
Back pain	14/38 (36.8%)
Bone pain	2/38 (5.3%)
Muscular weakness	2/38 (5.3%)
Musculoskeletal pain	2/38 (5.3%)
Pain in extremity	2/38 (5.3%)
Nervous system disorders
Dizziness	3/38 (7.9%)
Dysgeusia	4/38 (10.5%)
Headache	8/38 (21.1%)
Hypoaesthesia	3/38 (7.9%)
Neuropathy peripheral	2/38 (5.3%)
Somnolence	4/38 (10.5%)
Psychiatric disorders
Confusional state	2/38 (5.3%)
Depression	3/38 (7.9%)
Renal and urinary disorders
Renal failure acute	2/38 (5.3%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	2/38 (5.3%)
Dyspnoea	9/38 (23.7%)
Epistaxis	3/38 (7.9%)
Oropharyngeal pain	3/38 (7.9%)
Productive cough	3/38 (7.9%)
Skin and subcutaneous tissue disorders
Rash	3/38 (7.9%)
Vascular disorders
Hypertension	2/38 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.