Efficacy and Safety of LBH589B in Adult Patients With Refractory Chronic Myeloid Leukemia in Accelerated or Blast Phase

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00449761
• Collaborator: (none)
• Enrollment: 27
• Locations: 26
• Arm: 1
• Actual Duration (Months): 18.1
• Patients Per Site: 1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of LBH589B in adult patients with chronic myeloid leukemia who are in accelerated phase or blast phase (blast crisis) with resistant disease following treatment with at least two BCR-ABL tyrosine kinase inhibitors

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Chronic	Drug: LBH589	Phase 2

Detailed Description

study was designed to assess the hematologic response associated with treatment of oral panobinostat. Hematologic response is defined as the overall of complete hematologic response (CHR), and of no evidence of leukemia (NEL) and of the return to chronic phase (RTC). Hematologic responses were to be confirmed after 4 weeks, and all criteria listed below for each type of response were to be concomitantly met to result into a response.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicentre Study of Oral LBH589 in Patients With Accelerated Phase or Blast Phase (Blast Crisis) Chronic Myeloid Leukemia With Resistant Disease Following Treatment With at Least Two BCR-ABL Tyrosine Kinase Inhibitors
• Actual Study Start Date: Feb 23, 2007
• Actual Primary Completion Date: Jan 29, 2008
• Actual Study Completion Date: Aug 26, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Panobinostat Participants received panobinostat 20 milligrams (mg) orally once daily (OD), three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 milliliter (ml) of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.

Drug: LBH589; Other Names: Panobinostat

Outcome Measures

Primary Outcome Measures

1. Participants With Hematologic Response [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   The primary efficacy variable was hematologic response, a composite endpoint defined as the overall of complete hematologic response (CHR), and of no evidence of leukemia (NEL) and of the return to chronic phase (RTC).

Secondary Outcome Measures

1. Duration of Hematologic Response [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   Duration of hematologic response is defined as the time from the first documentation of the hematologic response to the date of the first documentation of the disease progression

2. Complete Cytogenetic Response (CCyR) Rate [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   Durations of complete cytogenetic response is defined as the time from the first documentation of the major/complete response to the first documentation of the disease progression.

3. Major (Complete/Partial) Cytogenetic Response Rate [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   Durations of major/complete cytogenetic response is defined as the time from the first documentation of the major/complete response to the first documentation of the disease progression.

4. Complete Cytogenetic Response (CCyR) and Overall (Complete/Partial/Minor/Minimal) Cytogenetic Response (OCyR) Rates [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   Cytogenetic response was assessed by bone marrow assessment based on the percentage of Ph+ metaphases by karyotype analysis on a bone marrow aspirate, was ideally assessed from a minimum of 20 metaphases in each bone marrow sample.

5. Duration of Major Cytogenetic Response [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   The duration of response was defined as the time between the first documented response to the date of discontinuation due to progressive disease (PD) or death.

6. Major (MMR) and Complete (CMR) Molecular Response Rates [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   Molecular response was defined as major (≤ 0.1% on the International Scale) and complete [absence of fusion gene of the BCR and ABL genes (BCR-ABL) on an quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay with a sensitivity of at least 4.5 logs below baseline].

7. BCR-ABL Mutations of Participants at Study Entry and, in Responding Participants and at the Time of Disease Progression [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   A fusion gene of the BCR and ABL genes (BCR-ABL) messenger ribose nucleic acid (mRNA) expression (molecular response) was performed by quantitative polymerase chain reaction (qPCR) and mutational analysis was performed by direct sequencing technology, and both analyses were performed by Genzyme.

8. Progression Free Survival (PFS) [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   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.

9. Overall Survival Time [From Start of the Study up to Study Termination (approximately up to 18 Months).]

   Overall survival time is defined as the time from the treatment start to the date of death due to any reason.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. QT Interval (QTc) in Participants Receiving Oral Panobinostat at Baseline and Change From Baseline to Extreme Value [From Start of the Study up to Study Termination (approximately up to 18 Months).]

    QTc monitoring was performed on specified days (Cycle1: Day1, 5 and 26), as well as a single pre-dose ECG once weekly during Cycle1: Week2 and Week3, Cycle2, and all subsequent cycles. Patient eligibility was ensured by a screening QTcF interval calculated by eResearchTechnology(eRT) prior to the baseline assessments. Treatment decisions were based on QTc determined by the automated reading at the investigational site (commonly used the Bazett's correction,QTcB) or measured and calculated by trained personnel at the site. Dosing relied on the investigator's assessment of the 6 baseline ECGs (the average of the 6pre-dose QTc intervals) performed prior to Cycle1/Day1 dosing, of the 3pre-dose ECGs during Cycle1:Day5 and 26, and of the single pre-dose ECGs performed once weekly for the remaining weeks of Cycle1 and subsequent cycles. The Baseline and Change From Baseline to Extreme Value QTcF interval for analysis was calculated by eRT based on the 6 baseline ECGs obtained on Cycle1/Day1.

16. Safety and Tolerability of Panobinostat [From Start of the Study up to Study Termination (approximately up to 18 Months).]

    Adverse Events (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

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Male or female patients aged ≥ 18 years old

• Diagnosis of Philadelphia chromosome positive accelerated or blast phase chronic myeloid leukemia defined as:

Accelerated phase - the presence of at least one of the following:

• ≥15% but <30% blasts in blood or bone marrow

• ≥30% blasts plus promyelocytes in peripheral blood or bone marrow (providing that <30% blasts present in bone marrow)

• ≥ 20% basophiles in the peripheral blood

• Thrombocytopenia <100 X 109 /L unrelated to sole therapy

Blast phase (blast crisis) - the presence of one of the following:

• ≥ 30% blasts in the blood, in bone marrow or both

• Extramedullary infiltrates of leukemic cells other than liver or spleen involvement

• Prior treatment with at least two a fusion gene of the BCR and ABL genes (BCR-ABL) tyrosine kinase inhibitors (i.e., imatinib, nilotinib, or dasatinib) and demonstrated resistance to the most recent kinase inhibitor therapy. Resistance to a BCR-ABL tyrosine kinase inhibitors (TKI) for this study was defined as:

• Progression from chronic phase to either accelerated phase or blast crisis

• Progression from accelerated phase to blast crisis

• No hematologic response (defined as not achieving complete hematologic response (CHR), no evidence of leukemia (NEL) or return to chronic phase (RTC)) within 3 months of starting therapy

• Increasing blast counts in peripheral blood of increasing marrow leukemic infiltrate (MLI, the percent marrow blasts multiplied by marrow cellularity)

• Patients with a history of intolerance to one BCR-ABL kinase inhibitors (defined as discontinuation of treatment due grade 3 or 4 adverse events related to treatment) will be considered eligible to enter the study if they demonstrate resistance to their most recent BCR-ABL kinase inhibitor. Intolerance was defined as discontinuation of treatment due to either grade 3 or 4 treatment-related Adverse Event (AE) or a grade 2 treatment-related AE persisting for ≥ one month or recurring more than three times despite dose reduction.

• Patients must have adequate laboratory values:

• Serum albumin ≥ 3g/dL

• Aspartate Aminotransferase (AST)/Serum Glutamate Oxalacetate Transaminase (SGOT) and Alanine Aminotransferase (ALT)/Serum Glutamate Pyruvate Transaminase (SGPT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to leukemic involvement

• Serum bilirubin ≤ 1.5 x ULN

• Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min

• Serum potassium, phosphorus, magnesium, and serum total calcium (corrected for serum albumin) or serum ionized calcium ≥ Lower Limit of Normal (LLN). Supplementation was allowed to correct potassium, calcium, and magnesium values prior to enrollment.

• Thyroid Stimulating Hormone (TSH) and free Thyroxine (T4) within normal limits (WNL) (patients may have been on thyroid hormone replacement)

• Baseline measurement of left ventricular ejection fraction [assessment of the hearts ability to pump effectively]

• Assessment of patients ability to perform every day activities. Assessment by the Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

Exclusion criteria:

• A candidate for hematopoietic stem cell transplantation

• Prior therapy with certain medications:

• Therapeutic doses of sodium warfarin or any other anti-vitamin K drug (low doses for line patency were allowed).

• Candidate for hematopoietic stem cell transplantation (HSCT)

• Prior histone deacetylase (HDAC) inhibitor treatment of Chronic Myelogenous Leukemia (CML)

• Concomitant use of drugs with a risk of causing QT complex (QTc) prolongation or torsades de pointes, CYP3A4/5 inhibitors, anti-cancer therapy or radiation therapy, valproic acid (within 5 days prior to study drug treatment or during the study), chemotherapy (within 3 weeks), immunotherapy (within 1 week), BCR-ABL kinase inhibitor ≤ 1 week of first treatment with panobinostat

• Patients who are in chronic phase chronic myeloid leukemia

• Impaired cardiac function or clinically significant cardiac diseases

• Concomitant use of drugs with a risk of possible risk of causing QTc prolongation or torsades de pointes

• Concomitant use of certain medications

• Impairment of Gastrointestinal (GI) function or GI disease

• Patients with unresolved diarrhea

• Women who are pregnant or breast feeding or women of childbearing potential not using an effective method of birth control

• Male patients whose sexual partners are women of child bearing potential not using effective birth control Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	University of Colorado Health Sciences Center/Anschutz Cancer Pavilion	Aurora	Colorado	United States	80010
3	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
4	Northwestern University Clinical Research Office	Chicago	Illinois	United States	60611
5	Rush University Medical Center	Chicago	Illinois	United States	60612
6	University Chicago Hospital	Chicago	Illinois	United States	60637
7	Indiana Blood and Marrow Institute/St. Francis Hospital	Beech Grove	Indiana	United States	46107
8	University of Michigan	Ann Arbor	Michigan	United States	48109
9	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
10	Hackensack University Medical Center/Oncology Research Dept.	Hackensack	New Jersey	United States	07601
11	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
12	University of Rochester Medical Center	Rochester	New York	United States	14642
13	Duke University Hospital	Durham	North Carolina	United States	27710
14	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
15	Oregon Health & Science University	Portland	Oregon	United States	97239
16	Emory University School of Medicine-Winship Cancer Institute	Nashville	Tennessee	United States	37212
17	Vanderbilt University Medical Center, Clinical Trials Center	Nashville	Tennessee	United States	37212
18	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
19	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
20	Novartis Investigative Site	Cologne		Germany
21	Novartis Investigative Site	Duesseldorf		Germany
22	Novartis Investigative Site	Hamburg		Germany
23	Novartis Investigative Site	Leipzig		Germany
24	Novartis Investigative Site	Mainz		Germany
25	Novartis Investigative Site	Mannheim		Germany
26	Novartis Investigative Site	Munich		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: NCT00449761
• Other Study ID Numbers: CLBH589B2211
• First Posted: Mar 21, 2007
• Last Update Posted: Jul 15, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by Novartis Pharmaceuticals: Refractory; Chronic Myeloid; Leukemia; accelerated phase; blast phase (blast crisis); adults; oral LBH589
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Panobinostat

Study Results

Participant Flow

Recruitment Details	The study was conducted at 20 centers in 7 countries.
Pre-assignment Detail	A total 27 Participants were enrolled in the study of which 27 participants discontinued the study treatment and 18 participants discontinued the study.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 milligrams (mg) orally once daily (OD), three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 milliliter (ml) of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Period Title: Overall Study
STARTED	27
COMPLETED	9
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Overall Participants	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.6 (12.38)
Sex: Female, Male (Count of Participants)
Female	13 48.1%
Male	14 51.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	22 81.5%
Black	4 14.8%
Other	1 3.7%

Outcome Measures

1. Primary Outcome

Title	Participants With Hematologic Response
Description	The primary efficacy variable was hematologic response, a composite endpoint defined as the overall of complete hematologic response (CHR), and of no evidence of leukemia (NEL) and of the return to chronic phase (RTC).
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

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. Population included all participants enrolled into the study. Enrolled participant were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated because of a lack of evidence of activity in the targeted participant population.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Duration of Hematologic Response
Description	Duration of hematologic response is defined as the time from the first documentation of the hematologic response to the date of the first documentation of the disease progression
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. 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 because of a lack of evidence of activity in the targeted Participant population. Because of a lack of evidence of hematologic response (primary objective), secondary efficacy endpoints were not analyzed.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

3. Secondary Outcome

Title	Complete Cytogenetic Response (CCyR) Rate
Description	Durations of complete cytogenetic response is defined as the time from the first documentation of the major/complete response to the first documentation of the disease progression.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. 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 because of a lack of evidence of activity in the targeted Participant population. Because of a lack of evidence of hematologic response (primary objective), secondary efficacy endpoints were not analyzed.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

4. Secondary Outcome

Title	Major (Complete/Partial) Cytogenetic Response Rate
Description	Durations of major/complete cytogenetic response is defined as the time from the first documentation of the major/complete response to the first documentation of the disease progression.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. 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 because of a lack of evidence of activity in the targeted Participant population. Because of a lack of evidence of hematologic response (primary objective), secondary efficacy endpoints were not analyzed.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

5. Secondary Outcome

Title	Complete Cytogenetic Response (CCyR) and Overall (Complete/Partial/Minor/Minimal) Cytogenetic Response (OCyR) Rates
Description	Cytogenetic response was assessed by bone marrow assessment based on the percentage of Ph+ metaphases by karyotype analysis on a bone marrow aspirate, was ideally assessed from a minimum of 20 metaphases in each bone marrow sample.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. 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 because of a lack of evidence of activity in the targeted Participant population. Because of a lack of evidence of hematologic response (primary objective), secondary efficacy endpoints were not analyzed.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

6. Secondary Outcome

Title	Duration of Major Cytogenetic Response
Description	The duration of response was defined as the time between the first documented response to the date of discontinuation due to progressive disease (PD) or death.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population was defined according to the intention-to-treat principle. 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 because of a lack of evidence of activity in the targeted Participant population. Because of a lack of evidence of hematologic response (primary objective), secondary efficacy endpoints were not analyzed.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

7. Secondary Outcome

Title	Major (MMR) and Complete (CMR) Molecular Response Rates
Description	Molecular response was defined as major (≤ 0.1% on the International Scale) and complete [absence of fusion gene of the BCR and ABL genes (BCR-ABL) on an quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay with a sensitivity of at least 4.5 logs below baseline].
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

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 because of a lack of evidence of activity in the targeted Participant 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

8. Secondary Outcome

Title	BCR-ABL Mutations of Participants at Study Entry and, in Responding Participants and at the Time of Disease Progression
Description	A fusion gene of the BCR and ABL genes (BCR-ABL) messenger ribose nucleic acid (mRNA) expression (molecular response) was performed by quantitative polymerase chain reaction (qPCR) and mutational analysis was performed by direct sequencing technology, and both analyses were performed by Genzyme.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

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 participants were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated because of a lack of evidence of activity in the targeted Participant population.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Count of Participants [Participants]	0 0%

9. 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 Study Termination (approximately up to 18 Months).

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 because of a lack of evidence of activity in the targeted Participant 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

10. Secondary Outcome

Title	Overall Survival Time
Description	Overall survival time is defined as the time from the treatment start to the date of death due to any reason.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

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 because of a lack of evidence of activity in the targeted Participant 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	0

11. 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 set (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 as part of a 4 week (28 day). Panobinostat was administered at the same time each morning, and with an 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Day 1	1.5
Day 8	1.5

12. 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Day 1	13.5 (7.0)
Day 8	20.9 (15.0)

13. 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	12
Day 1	139 (61)
Day 8	148 (69)

14. 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Day 1	1.9 (2.4)
Day 8	4.7 (8.2)

15. 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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Day 1	23.9
Day 8	24.1

16. Secondary Outcome

Title	QT Interval (QTc) in Participants Receiving Oral Panobinostat at Baseline and Change From Baseline to Extreme Value
Description	QTc monitoring was performed on specified days (Cycle1: Day1, 5 and 26), as well as a single pre-dose ECG once weekly during Cycle1: Week2 and Week3, Cycle2, and all subsequent cycles. Patient eligibility was ensured by a screening QTcF interval calculated by eResearchTechnology(eRT) prior to the baseline assessments. Treatment decisions were based on QTc determined by the automated reading at the investigational site (commonly used the Bazett's correction,QTcB) or measured and calculated by trained personnel at the site. Dosing relied on the investigator's assessment of the 6 baseline ECGs (the average of the 6pre-dose QTc intervals) performed prior to Cycle1/Day1 dosing, of the 3pre-dose ECGs during Cycle1:Day5 and 26, and of the single pre-dose ECGs performed once weekly for the remaining weeks of Cycle1 and subsequent cycles. The Baseline and Change From Baseline to Extreme Value QTcF interval for analysis was calculated by eRT based on the 6 baseline ECGs obtained on Cycle1/Day1.
Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).

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 because of a lack of evidence of activity in the targeted Participant population.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 20 mg orally OD, three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Baseline	396.6 (20.10)
Change from Baseline	24.5 (9.58)

17. Secondary Outcome

Title	Safety and Tolerability of Panobinostat
Description	Adverse Events (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 Study Termination (approximately up to 18 Months).

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 as part of a 4 week (28 day) treatment cycle. Panobinostat was administered at the same time each morning, and with an 8oz/240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
Measure Participants	27
Participants with Adverse Events	27 100%
Deaths	16 59.3%
Serious Adverse Events	13 48.1%

Adverse Events

Time Frame	From Start of the Study up to Study Termination (approximately up to 18 Months).
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 as part of a 4 week (28 day). Panobinostat was administered at the same time each morning, and with an 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue this treatment until an unacceptable toxicity that precludes further treatment was experienced, or until disease progression.
All Cause Mortality
	Panobinostat
	Affected / at Risk (%)	# Events
Total	16/27 (59.3%)
Serious Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	13/27 (48.1%)
Blood and lymphatic system disorders
Febrile neutropenia	1/27 (3.7%)
Haemorrhagic diathesis	1/27 (3.7%)
Neutropenia	2/27 (7.4%)
Thrombocytopenia	4/27 (14.8%)
General disorders
Asthenia	1/27 (3.7%)
Catheter site haemorrhage	2/27 (7.4%)
General physical health deterioration	1/27 (3.7%)
Pyrexia	4/27 (14.8%)
Infections and infestations
Pneumonia	1/27 (3.7%)
Pseudomonal bacteraemia	1/27 (3.7%)
Sepsis	1/27 (3.7%)
Injury, poisoning and procedural complications
Post procedural haemorrhage	1/27 (3.7%)
Subdural haematoma	1/27 (3.7%)
Investigations
Platelet count decreased	1/27 (3.7%)
White blood cell count increased	1/27 (3.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Central nervous system leukaemia	1/27 (3.7%)
Nervous system disorders
Aphasia	1/27 (3.7%)
Cerebral haemorrhage	1/27 (3.7%)
Cerebral infarction	1/27 (3.7%)
Coma	1/27 (3.7%)
Haemorrhagic cerebral infarction	1/27 (3.7%)
Syncope	1/27 (3.7%)
Psychiatric disorders
Mental status changes	1/27 (3.7%)
Renal and urinary disorders
Renal failure	1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/27 (3.7%)
Vascular disorders
Thrombophlebitis	1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Blood and lymphatic system disorders
Anaemia	10/27 (37%)
Leukocytosis	4/27 (14.8%)
Neutropenia	2/27 (7.4%)
Thrombocytopenia	10/27 (37%)
Cardiac disorders
Tachycardia	3/27 (11.1%)
Gastrointestinal disorders
Abdominal pain	4/27 (14.8%)
Abdominal pain upper	3/27 (11.1%)
Constipation	2/27 (7.4%)
Diarrhoea	10/27 (37%)
Nausea	6/27 (22.2%)
Stomatitis	3/27 (11.1%)
Vomiting	4/27 (14.8%)
General disorders
Asthenia	3/27 (11.1%)
Chills	2/27 (7.4%)
Fatigue	3/27 (11.1%)
Oedema peripheral	4/27 (14.8%)
Pain	3/27 (11.1%)
Pyrexia	7/27 (25.9%)
Infections and infestations
Bacteraemia	2/27 (7.4%)
Pneumonia	2/27 (7.4%)
Upper respiratory tract infection	2/27 (7.4%)
Urinary tract infection	2/27 (7.4%)
Investigations
White blood cell count increased	2/27 (7.4%)
Metabolism and nutrition disorders
Hyperkalaemia	3/27 (11.1%)
Hyperuricaemia	5/27 (18.5%)
Hypocalcaemia	2/27 (7.4%)
Hypokalaemia	5/27 (18.5%)
Hyponatraemia	3/27 (11.1%)
Musculoskeletal and connective tissue disorders
Back pain	3/27 (11.1%)
Bone pain	2/27 (7.4%)
Pain in extremity	3/27 (11.1%)
Nervous system disorders
Dizziness	2/27 (7.4%)
Headache	2/27 (7.4%)
Renal and urinary disorders
Renal failure	2/27 (7.4%)
Urinary incontinence	2/27 (7.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/27 (14.8%)
Epistaxis	2/27 (7.4%)
Hypoxia	2/27 (7.4%)
Pleural effusion	2/27 (7.4%)

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.