Panobinostat (LBH589) and Imatinib Mesylate in Treating Patients With Previously Treated Chronic Phase Chronic Myelogenous Leukemia

A Phase I Dose Escalation Study of LBH589 in Combination With Imatinib Mesylate for Patients With Chronic Myeloid Leukemia in Cytogenetic Remission With Residual Disease Detectable by Q-PCR

RATIONALE: Panobinostat and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of panobinostat when given together with imatinib in treating patients with previously treated chronic phase chronic myelogenous leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: imatinib mesylate; Drug: panobinostat; Genetic: polymerase chain reaction; Genetic: protein expression analysis; Genetic: western blotting; Other: flow cytometry; Other: laboratory biomarker analysis; Other: pharmacological study

Detailed Description

OBJECTIVES:

Primary

• To determine the safety and tolerability of LBH589 given in combination with imatinib mesylate in CML patients who are in Major Cytogenetic Remission (MCR) with residual BCR-ABL positive cells after at least 1 year of daily imatinib mesylate treatment.
• To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of LBH589 given in combination with imatinib mesylate in CML patients.

Secondary

• To study the effect of LBH589 given in combination with imatinib mesylate on cytogenetic response status and BCR-ABL levels in CML patients in major cytogenetic remission on imatinib mesylate treatment.

Tertiary

• To study the effect of LBH589 given in combination with imatinib mesylate on residual BCR-ABL positive primitive progenitors in CML patients in major cytogenetic remission on imatinib mesylate treatment.

OUTLINE: This is dose-escalation study of panobinostat.

Patients receive oral panobinostat once daily on days 1, 3 and 5; 8, 10, and 12; 15, 17, and 19; and 22, 24, and 26. Patients also receive oral imatinib mesylate once daily on days 1-28. Treatment repeats every 21 or 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month and then every 3 months for up to 1 year.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Medical Center
    • South Pasadena, California, United States, 91030
      • South Pasadena Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• CML CP patients who have been treated with and tolerated Imatinib for 1 year or more, have achieved at least major cytogenetic response and continue to be BCR-ABL positive (Patients should be receiving Imatinib at a dose of 400 daily at the time of entry into the study)
• ANC and PLT need to be in the normal range
• Serum albumin >= 3g/dL
• AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal (ULN)
• Serum bilirubin =< 1.5 x ULN
• Serum creatinine =< 1.5 x ULN or 24-hour creatinine clearance >= 50 ml/min
• Serum potassium >= lower limit of normal (LLN)
• Serum phosphorus >= LLN
• Serum total calcium (corrected for serum albumin) or serum ionized calcium >= LLN
• Serum magnesium >= LLN
• ECOG performance status of =< 2

Exclusion Criteria:

• Prior treatment with an HDAC inhibitor
• Patient who have been treated with Imatinib < 1 year or patients are currently being treated with Imatinib at a dose > 400 mg daily
• Impaired cardiac function including any one of the following: Screening ECG with a QTc > 450 msec; Patients with congenital long QT syndrome; History or presence of sustained ventricular tachycardia; Any history of ventricular fibrillation or torsades de pointes; Bradycardia defined as heart rate < 50 beats per minute (patients with a pacemaker and heart rate >= 50 beats per minute are eligible); Patients with a myocardial infarction or unstable angina within 6 months of study entry; Congestive heart failure (NY Heart Association class III or IV); Right bundle branch block and left anterior hemiblock (bifascicular block)
• Uncontrolled hypertension
• Concomitant use of drugs with a risk of prolonging the QT interval or inducing torsades de pointes
• Concomitant use of CYP3A4 inhibitors
• Patients with unresolved diarrhea > CTCAE grade 1
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589
• Other concurrent severe and/or uncontrolled medical conditions
• Patients who have received chemotherapy, any investigational drug or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Concomitant use of any other anti-cancer therapy or radiation therapy
• Patients being treated with Coumadin (unless patients who require anticoagulation can be switched to a low-molecular weight or standard heparin)
• Female patients who are pregnant or breast feeding or patients of reproductive potential not willing to use a double method of contraception including a barrier method (i.e. condom) during the study and 3 months after the end of treatment (Women of childbearing potential [WOCBP] must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589)
• Male patients whose sexual partners are WOCBP not willing to use a double method of contraception including condom during the study and 3 months after the end of treatment
• Patients with a history of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin
• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
• Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (panobinostat, imatinib mesylate); Patients receive oral panobinostat once daily on days 1, 3 and 5; 8, 10, and 12; 15, 17, and 19; and 22, 24, and 26. Patients also receive oral imatinib mesylate once daily on days 1-28. Treatment repeats every 21 or 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: imatinib mesylate; Given orally; Other Names: Gleevec; CGP 57148; Glivec; Drug: panobinostat; Given orally; Other Names: LBH589; Faridak; HDAC inhibitor LBH589; histone deacetylase inhibitor LBH589; Genetic: polymerase chain reaction; Testing; Genetic: protein expression analysis; Testing; Genetic: western blotting; Testing; Other: flow cytometry; Testing; Other: laboratory biomarker analysis; Testing; Other: pharmacological study; Testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of histone deacetylase inhibitor LBH589 in combination with imatinib mesylate	1 month
Safety and tolerability of histone deacetylase inhibitor LBH589 in combination with imatinib mesylate	4 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Effect of treatment with histone deacetylase inhibitor LBH589 in combination with imatinib mesylate on cytogenetic response status and BCR-Abl levels	4 months
Effect of treatment with histone deacetylase inhibitor LBH589 in combination with imatinib mesylate on residual BCR-Abl positive primitive progenitors	4 months

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ravi Bhatia, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: May 28, 2008
• First Submitted That Met QC Criteria: May 28, 2008
• First Posted (Estimate): May 29, 2008

Study Record Updates

• Last Update Posted (Estimate): August 15, 2014
• Last Update Submitted That Met QC Criteria: August 14, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: chronic phase chronic myelogenous leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia; Leukemia, Myeloid, Chronic-Phase; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate; Histone Deacetylase Inhibitors; Panobinostat
• Other Study ID Numbers: 07203; P30CA033572 (U.S. NIH Grant/Contract); NOVARTIS-CSTI571AUS275T; CDR0000596065 (Registry Identifier: PDQ); NCI-2010-00528 (Registry Identifier: NCI CTRP)