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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00686218
• Other study ID #: 07203
• Secondary ID: P30CA033572NOVAR
• Status: Completed
• Phase: Phase 1
• First received: May 28, 2008
• Last updated: August 14, 2014
• Start date: May 2008
• Est. completion date: August 2014

Study information

• Verified date: August 2014
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: August 2014
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase

Intervention

Drug:
• imatinib mesylate
Given orally
• panobinostat
Given orally

Genetic:
• polymerase chain reaction
Testing
• protein expression analysis
Testing
• western blotting
Testing

Other:
• flow cytometry
Testing
• laboratory biomarker analysis
Testing
• pharmacological study
Testing

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington
United States	South Pasadena Cancer Center	South Pasadena	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of histone deacetylase inhibitor LBH589 in combination with imatinib mesylate		1 month	Yes
Primary	Safety and tolerability of histone deacetylase inhibitor LBH589 in combination with imatinib mesylate		4 months	Yes
Secondary	Effect of treatment with histone deacetylase inhibitor LBH589 in combination with imatinib mesylate on cytogenetic response status and BCR-Abl levels		4 months	No
Secondary	Effect of treatment with histone deacetylase inhibitor LBH589 in combination with imatinib mesylate on residual BCR-Abl positive primitive progenitors		4 months	No