Efficacy and Safety of LBH589B in Adult Patients With Refractory Chronic Myeloid Leukemia in Accelerated or Blast Phase
- Registration Number
- NCT00449761
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 27
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Panobinostat LBH589 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.
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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.
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 \[absence of fusion gene of the BCR and ABL genes (BCR-ABL) on an quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay with a sensitivity of at least 4.5 logs below baseline\].
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
Trial Locations
- Locations (20)
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Hackensack University Medical Center/Oncology Research Dept.
🇺🇸Hackensack, New Jersey, United States
Indiana Blood and Marrow Institute/St. Francis Hospital
🇺🇸Beech Grove, Indiana, United States
Novartis Investigative Site
🇩🇪Munich, Germany
Northwestern University Clinical Research Office
🇺🇸Chicago, Illinois, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Mayo Clinic Cancer Center
🇺🇸Rochester, Minnesota, United States
University of Colorado Health Sciences Center/Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Rocky Mountain Cancer Center
🇺🇸Denver, Colorado, United States
Duke University Hospital
🇺🇸Durham, North Carolina, United States
Emory University School of Medicine-Winship Cancer Institute
🇺🇸Nashville, Tennessee, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Vanderbilt University Medical Center, Clinical Trials Center
🇺🇸Nashville, Tennessee, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University Chicago Hospital
🇺🇸Chicago, Illinois, United States