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

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of LBH589B in adult patients with chronic phase chronic myeloid leukemia with resistant disease following treatment with at least two BCR-ABL tyrosine kinase inhibitors

Official Title
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A Phase II, Multicentre Study of Oral LBH589 in Patients With Chronic Phase Chronic Myeloid Leukemia With Resistant Disease Following Treatment With at Least Two Fusion Gene of the BCR and ABL Genes (BCR-ABL) Tyrosine Kinase Inhibitors

Conditions
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Chronic Myeloid Leukemia in Chronic Phase

Intervention / Treatment
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* Drug: LBH589


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients aged ≥ 18 years old Diagnosis of Philadelphia chromosome positive, chronic phase chronic myeloid leukemia Prior treatment with at least two BCR-ABL tyrosine kinase inhibitors with demonstrated resistance to the most recent kinase inhibitor therapy. Patients with a history of intolerance to one BCR-ABL kinase inhibitors will be considered eligible to enter the study if they demonstrate resistance to their most recent BCR-ABL kinase inhibitor. Patients who are intolerant of at least 2 BCR-ABL kinase inhibitors will be considered eligible to enter this study if they also demonstrate resistance to or intolerance of interferon-alpha (IFN-α) by the same criteria defined above. Patients must have adequate laboratory values: Hematology: absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 8.0 g/dL. Serum chemistry: albumin ≥ 3 g/dL; aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to leukemic involvement; bilirubin ≤ 1.5 x ULN; creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 mL/min; potassium, phosphorus, magnesium and total calcium (corrected for serum albumin) or serum ionized calcium ≥ lower limit of normal (LLN), thyroid stimulating hormone (TSH) and free T4 (thyroxine) within normal limits. Note: Potassium, calcium, and magnesium supplements to correct values that are < LLN, were allowed when documented as corrected prior to enrollment. 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 Exclusion criteria: A candidate for hematopoietic stem cell transplantation Prior therapy with certain medications Patients with a prior history of accelerated phase or blast crisis CML Impaired cardiac function or clinically significant cardiac diseases Concomitant use of certain medications. Therapeutic doses of sodium warfarin or any other anti-vitamin K drug (low doses for line patency were allowed). Prior HDACi treatment of CML, concomitant use of drugs with a risk of causing QT interval (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 or major surgery (within 3 weeks), immunotherapy (within 1 week), BCR-ABL tyrosine kinase inhibitors (TKI) ≤ 1 week of first treatment with panobinostat Impairment of GI function or GI disease Patients with unresolved diarrhea Patients who have received chemotherapy, any investigational drugs or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy Patients who have received a BCR-ABL tyrosine-kinase inhibitor within 1 week of first treatment with LBH589 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat (LBH589)<br>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 8oz/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. | Drug: LBH589<br> <br> * Other names: Panobinostat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major (Complete/Partial) Cytogenetic Response (MCyR) Rate | 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). | From Start of the Study up to End of Study (approximately up to 19 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Major (Complete/Partial) Cytogenetic Response (MCyR) Rate | 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. | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| Complete Hematologic Response (CHR) Rate | 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. | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| Complete Cytogenetic Response (CCyR) and Overall (Complete/Partial/Minor/Minimal) Cytogenetic Response (OCyR) Rates | 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. | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| Major (MMR) and Complete (CMR) Molecular Response Rates | 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]. | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| BCR-ABL Mutations of Participants at Study Entry and, in Responding Participants and at the Time of Disease Progression | 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. | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| Progression Free Survival Time | 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 | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| Maximum Plasma Concentration (Cmax) of Panobinostat | 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). | Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1 | 
| Time to Peak Concentration (Tmax) of Panobinostat | Time to reach peak or maximum plasma drug concentration following drug administration. Tmax will be reported in units of hour (hr). | Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1 | 
| Area Under the Plasma Concentration (AUC0-24) of Panobinostat | 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. | Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1 | 
| Last Observed Plasma Concentration (Clast) of Panobinostat | Clast is defined as the Last observed (quantifiable) plasma concentration at last sampling time. | Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1 | 
| Time of Clast (Tlast) of Panobinostat | Time of last sampling point. Tlast will be reported in units of hr | Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1 | 
| QT Interval (QTc) in Participants Receiving Oral Panobinostat at Baseline and Change From Baseline to Extreme Value | 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. | From Start of the Study up to End of Study (approximately up to 19 Months) | 
| Safety and Tolerability Profile of Oral Panobinostat | 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. | From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory Chronic Myeloid Leukemia in Chronic Phase, adults, oral LBH589