Trial Outcomes & Findings for Efficacy and Safety of LBH589 in Adult Patients With Refractory Chronic Myeloid Leukemia (CML) in Chronic Phase (NCT NCT00451035)

Last Updated: 2021-07-15

Results Overview

The CyR, 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. The CyR was defined as: major response including complete (CCyR; 0% Ph+ metaphases) or partial (PCyR; 1 to 35% Ph+ metaphases), minor (36 to 65% Ph+ metaphases), minimal (66 to 95% Ph+ metaphases) or none (96 to 100% Ph+ metaphases).

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

29 participants

Primary outcome timeframe

From Start of the Study up to End of Study (approximately up to 19 Months)

Results posted on

2021-07-15

Participant Flow

The study was conducted at 19 centers in multiple countries.

A total of 29 participants were enrolled, of which 29 participants discontinued the study treatment and 17 participants discontinued the study.

Participant milestones

Participant milestones
Measure	Panobinostat (LBH589) Participants were administered panobinostat 20 milligram (mg) orally once a day (OD) three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 milliliter (ml) of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Overall Study STARTED	29
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Panobinostat (LBH589) Participants were administered panobinostat 20 milligram (mg) orally once a day (OD) three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 milliliter (ml) of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Overall Study Disease progression	11
Overall Study Death	3
Overall Study New anti-neoplastic therapy	3

Baseline Characteristics

Efficacy and Safety of LBH589 in Adult Patients With Refractory Chronic Myeloid Leukemia (CML) in Chronic Phase

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Panobinostat (LBH589) n=29 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Age, Continuous	53.8 years STANDARD_DEVIATION 12.22 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	26 Participants n=5 Participants
Race/Ethnicity, Customized Black	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

Population: Full Analysis Set (FAS) consisted of all enrolled participants who have received at least one dose of study medication. 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.

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=29 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Major (Complete/Partial) Cytogenetic Response (MCyR) Rate	0 Participants

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

Population: The FAS consisted of all enrolled participants who have received at least one dose of study medication. 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

CHR was defined by meeting all criteria: white blood cell count \< 10 x 109/L, platelet count \< 450 x 109/L, myelocytes and metamyelocytes in peripheral blood \< 5%, basophils in peripheral blood ≤ 5%, no myeloblasts or promyelocytes in peripheral blood, and no evidence of extramedullary involvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

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.

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=19 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
BCR-ABL Mutations of Participants at Study Entry and, in Responding Participants and at the Time of Disease Progression	0 Participants

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

Progression-free survival time is defined as the time from the treatment start to the first documentation of the disease progression or the date of death, whichever occurs first

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1

Population: The analysis was performed on Pharmacokinetic (PK) 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.

Cmax is defined as the Maximum (peak) plasma drug concentration after single dose administration. Cmax will be reported in units of nanogram/milliliter (ng/ML).

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=16 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Maximum Plasma Concentration (Cmax) of Panobinostat	9.1 ng/mL Standard Deviation 4.01

SECONDARY outcome

Timeframe: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1

Population: The analysis was performed on PK 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.

Time to reach peak or maximum plasma drug concentration following drug administration. Tmax will be reported in units of hour (hr).

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=16 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Time to Peak Concentration (Tmax) of Panobinostat	1.5 hr Interval 0.2 to 3.6

SECONDARY outcome

Timeframe: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1

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.

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=12 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Area Under the Plasma Concentration (AUC0-24) of Panobinostat	96.0 ng*hr/mL Standard Deviation 41.37

SECONDARY outcome

Timeframe: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1

Clast is defined as the Last observed (quantifiable) plasma concentration at last sampling time.

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=19 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Last Observed Plasma Concentration (Clast) of Panobinostat	1.8 ng/mL Standard Deviation 2.02

SECONDARY outcome

Timeframe: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1

Time of last sampling point. Tlast will be reported in units of hr

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=19 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Time of Clast (Tlast) of Panobinostat	24.7 hr Standard Deviation 16.19

SECONDARY outcome

Timeframe: From Start of the Study up to End of Study (approximately up to 19 Months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=29 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
QT Interval (QTc) in Participants Receiving Oral Panobinostat at Baseline and Change From Baseline to Extreme Value Baseline	403.1 ms Standard Deviation 23.45
QT Interval (QTc) in Participants Receiving Oral Panobinostat at Baseline and Change From Baseline to Extreme Value Change from Baseline	29.1 ms Standard Deviation 23.91

SECONDARY outcome

Timeframe: From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months)

Population: 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.

Adverse events (AEs) 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 (SAEs) 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.

Outcome measures

Outcome measures
Measure	Panobinostat (LBH589) n=29 Participants Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Panobinostat were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Safety and Tolerability Profile of Oral Panobinostat AEs	28 Participants
Safety and Tolerability Profile of Oral Panobinostat SAEs	4 Participants
Safety and Tolerability Profile of Oral Panobinostat Deaths	3 Participants
Safety and Tolerability Profile of Oral Panobinostat AEs leading to discontinuation	6 Participants

Adverse Events

Panobinostat

Serious events: 4 serious events

Other events: 26 other events

Deaths: 3 deaths

Serious adverse events

Serious adverse events
Measure	Panobinostat n=29 participants at risk Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Treatment were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Blood and lymphatic system disorders Leukocytosis	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Blood and lymphatic system disorders Splenic infarction	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Cardiac disorders Cardiac failure	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Gastrointestinal haemorrhage	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
General disorders Pyrexia	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Investigations Electrocardiogram QT prolonged	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Vascular disorders Deep vein thrombosis	3.4% 1/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.

Other adverse events

Other adverse events
Measure	Panobinostat n=29 participants at risk Participants were administered panobinostat 20 mg orally OD three times a week as part of a 4 week (28 day) treatment cycle. Treatment were administered at the same time each morning with 240 ml of water after a fasting period of at least two hours (water was allowed). Participants could continue treatment until they experienced unacceptable toxicity or disease progression.
Blood and lymphatic system disorders Anaemia	20.7% 6/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Blood and lymphatic system disorders Neutropenia	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Blood and lymphatic system disorders Thrombocytopenia	24.1% 7/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Abdominal pain upper	6.9% 2/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Constipation	13.8% 4/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Diarrhoea	24.1% 7/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Dyspepsia	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Nausea	34.5% 10/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Gastrointestinal disorders Vomiting	17.2% 5/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
General disorders Asthenia	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
General disorders Chills	6.9% 2/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
General disorders Fatigue	27.6% 8/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
General disorders Oedema peripheral	17.2% 5/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
General disorders Pyrexia	17.2% 5/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Infections and infestations Nasopharyngitis	6.9% 2/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Investigations White blood cell count increased	13.8% 4/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Metabolism and nutrition disorders Anorexia	17.2% 5/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Metabolism and nutrition disorders Hypertriglyceridaemia	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Metabolism and nutrition disorders Hyperuricaemia	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Arthralgia	6.9% 2/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Bone pain	6.9% 2/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Myalgia	13.8% 4/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Nervous system disorders Headache	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Cough	13.8% 4/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Dry skin	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Rash	10.3% 3/29 • From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months). Safety population consisted of all patients who received at least one dose of study medication and had one valid post-baseline assessment.

Additional Information

Study Director

Novartis pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place