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

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).

Time frame: 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.

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, 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.

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 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.

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 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.

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.

Time frame: 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.

Time frame: 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.

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

Time frame: 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.

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 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.

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).

Time frame: 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.

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

Time frame: 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.

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 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.

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.

Time frame: 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.

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

Time frame: 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).

Time frame: 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.