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

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

Sponsors

Lead sponsor: City of Hope Medical Center

Collaborator: National Cancer Institute (NCI)

Source City of Hope Medical Center
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.

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.

Overall Status Completed
Start Date May 2008
Completion Date August 2014
Primary Completion Date March 2013
Phase Phase 1
Study Type Interventional
Primary 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
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
Enrollment 9
Condition
Intervention

Intervention type: Drug

Intervention name: imatinib mesylate

Description: Given orally

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Drug

Intervention name: panobinostat

Description: Given orally

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Genetic

Intervention name: polymerase chain reaction

Description: Testing

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Genetic

Intervention name: protein expression analysis

Description: Testing

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Genetic

Intervention name: western blotting

Description: Testing

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Other

Intervention name: flow cytometry

Description: Testing

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Other

Intervention name: laboratory biomarker analysis

Description: Testing

Arm group label: Treatment (panobinostat, imatinib mesylate)

Intervention type: Other

Intervention name: pharmacological study

Description: Testing

Arm group label: Treatment (panobinostat, imatinib mesylate)

Eligibility

Criteria:

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

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Ravi Bhatia, MD Principal Investigator City of Hope Medical Center
Location
facility
City of Hope Medical Center | Duarte, California, 91010-3000, United States
South Pasadena Cancer Center | South Pasadena, California, 91030, United States
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle, Washington, 98109, United States
Location Countries

United States

Verification Date

August 2014

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Arm group label: Treatment (panobinostat, imatinib mesylate)

Arm group type: Experimental

Description: 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.

Study Design Info

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov