Clinical trial NCT00451035: Efficacy and Safety of LBH589 in Adult Patients With Refractory Chronic Myeloid Leukemia (CML) in Chronic Phase
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia in Chronic Phase
Keywords: Refractory Chronic Myeloid Leukemia in Chronic Phase
adults
oral LBH589
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2007-03-22
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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:

  1. Hematology: absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 8.0 g/dL.
  2. 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

Primary outcomes:
measure: Major (Complete/Partial) Cytogenetic Response (MCyR) Rate
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
Secondary outcomes:
measure: Duration of Major (Complete/Partial) Cytogenetic Response (MCyR) Rate
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: Complete Hematologic Response (CHR) Rate
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: Complete Cytogenetic Response (CCyR) and Overall (Complete/Partial/Minor/Minimal) Cytogenetic Response (OCyR) Rates
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: Major (MMR) and Complete (CMR) Molecular Response Rates
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: BCR-ABL Mutations of Participants at Study Entry and, in Responding Participants and at the Time of Disease Progression
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: Progression Free Survival Time
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: Maximum Plasma Concentration (Cmax) of Panobinostat
timeFrame: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1
measure: Time to Peak Concentration (Tmax) of Panobinostat
timeFrame: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1
measure: Area Under the Plasma Concentration (AUC0-24) of Panobinostat
timeFrame: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1
measure: Last Observed Plasma Concentration (Clast) of Panobinostat
timeFrame: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1
measure: Time of Clast (Tlast) of Panobinostat
timeFrame: Pre-dose, and 0.25, 1-2, 3-4, 24, and 48 hours post-dose on Day 1
measure: QT Interval (QTc) in Participants Receiving Oral Panobinostat at Baseline and Change From Baseline to Extreme Value
timeFrame: From Start of the Study up to End of Study (approximately up to 19 Months)
measure: Safety and Tolerability Profile of Oral Panobinostat
timeFrame: From Start of the Study up to 28 Days After the last dose of Study Drug (approximately up to 19 Months)
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Godinne
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Cologne
country: Germany
facility: Novartis Investigative Site
city: Dusseldorf
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
city: Munich
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticlas
role: STUDY_DIRECTOR
References:
citation: Savelieva M, Woo MM, Schran H, Mu S, Nedelman J, Capdeville R. Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors. Eur J Clin Pharmacol. 2015 Jun;71(6):663-672. doi: 10.1007/s00228-015-1846-7. Epub 2015 May 5.