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

Study Overview
=================
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

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.

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

Conditions
-----------------
Leukemia, Myeloid, Chronic

Intervention / Treatment
-----------------
* Drug: LBH589


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat<br>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<br> <br> * Other names: Panobinostat;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Hematologic Response | 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). | From Start of the Study up to Study Termination (approximately up to 18 Months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Hematologic Response | 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 | From Start of the Study up to Study Termination (approximately up to 18 Months). | 
| Complete Cytogenetic Response (CCyR) Rate | 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. | From Start of the Study up to Study Termination (approximately up to 18 Months). | 
| Major (Complete/Partial) Cytogenetic Response Rate | 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. | From Start of the Study up to Study Termination (approximately up to 18 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 Study Termination (approximately up to 18 Months). | 
| Duration of Major Cytogenetic Response | 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 Study Termination (approximately up to 18 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 Study Termination (approximately up to 18 Months). | 
| BCR-ABL Mutations of Participants at Study Entry and, in Responding Participants and at the Time of Disease Progression | 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. | From Start of the Study up to Study Termination (approximately up to 18 Months). | 
| Progression Free Survival (PFS) | 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. | From Start of the Study up to Study Termination (approximately up to 18 Months). | 
| Overall Survival Time | Overall survival time is defined as the time from the treatment start to the date of death due to any reason. | From Start of the Study up to Study Termination (approximately up to 18 Months). | 
| Time to Peak Concentration (Tmax) of Panobinostat | 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. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Maximum Plasma Concentration (Cmax) of Panobinostat | 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. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| 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, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Last Observed Plasma Concentration (Clast) of Panobinostat | Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Time of Clast (Tlast) of Panobinostat | 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. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| 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 Study Termination (approximately up to 18 Months). | 
| Safety and Tolerability of Panobinostat | 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 | From Start of the Study up to Study Termination (approximately up to 18 Months). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Refractory, Chronic Myeloid, Leukemia, accelerated phase, blast phase (blast crisis), adults, oral LBH589