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

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.

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