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

Sponsor

City of Hope Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT00686218

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	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	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

9 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2008

Actual Primary Completion Date :

Mar 1, 2013

Actual Study Completion Date :

Aug 1, 2014

Arms and Interventions

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: CGP 57148 Gleevec Glivec Drug: panobinostat Given orally Other Names: Faridak HDAC inhibitor LBH589 histone deacetylase inhibitor LBH589 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

Arm

Intervention/Treatment

Experimental: Treatment (panobinostat, imatinib mesylate)

Drug: imatinib mesylate

Given orally

Other Names:

CGP 57148

Gleevec

Glivec

Drug: panobinostat

Given orally

Other Names:

Faridak

HDAC inhibitor LBH589

histone deacetylase inhibitor LBH589

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

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010-3000
2	South Pasadena Cancer Center	South Pasadena	California	United States	91030
3	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109