Panobinostat and Epirubicin in Treating Patients With Metastatic Malignant Solid Tumors

OBJECTIVES:

Primary

- To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended
phase II dose of panobinostat when administered with epirubicin hydrochloride in
patients with metastatic malignant solid tumors.

Secondary

- To determine the correlation between the pharmacokinetic profile of panobinostat drug
levels and the pharmacodynamic effect of panobinostat on histone acetylation in
peripheral blood mononuclear cells (PBMCs).

- To determine the effect of panobinostat on histone acetylation and chromatin remodeling
proteins (HP-1, DNMT-1, SMC1-5, Topo II).

- To determine the relevance of HDAC1, HDAC2, HDAC3, and HDAC6 expression in PBMCs as a
pharmacological marker and in biopsied tumors as a predictive marker for response in
patients treated at the MTD.

- To document any objective response in these patients.

OUTLINE: This is a dose-escalation study of panobinostat.

Patients receive oral panobinostat on days 1, 3, and 5 and epirubicin hydrochloride IV on
day 5. Treatment repeats every 21 days for up to 10 courses in the absence of disease
progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during course 1 for
panobinostat pharmacokinetic studies. Patients enrolled in the dose expansion cohort also
undergo collection of tumor tissue samples by fine needle aspiration at baseline and on day
5 of course 1 (after panobinostat infusion). Blood and tissue samples are analyzed for
histone acetylation, chromatin remodeling genes and proteins (HP-1, DNMT-1, SMC1-5, Topo
II), and HDAC enzyme expression by immunofluorescence and western blotting.

DISEASE CHARACTERISTICS:

- Cytologically or histologically confirmed solid tumor malignancy for which no
curative therapy exists

- Metastatic disease

- Measurable or evaluable disease (i.e., elevated CA-125 or elevated PSA for patients
with ovarian cancer or prostate cancer, respectively)

- Disease amenable to biopsy AND patient willing to undergo biopsies (for patients
enrolled in the dose expansion cohort only)

- No uncontrolled CNS metastasis

- Stable CNS metastasis allowed provided patient has undergone complete surgical
resection, gamma knife radiotherapy (for isolated lesions) or whole-brain
radiotherapy AND the metastasis has been stable for ≥ 6 weeks

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- WBC > 3,000/mm³

- ANC > 1,500/mm³

- Hemoglobin > 9.0 g/dL (RBC transfusion allowed)

- Platelet count > 100,000/mm³

- AST/ALT ≤ 1.5 times upper limit of normal (ULN)

- Serum bilirubin ≤ 1.3 times ULN

- Serum creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min by 24-hour urine
collection

- Total serum calcium (corrected for serum albumin) or ionized calcium ≥ lower limit of
normal

- Serum potassium ≥ 4.0 mEq/L (supplementation allowed)

- Serum magnesium normal (supplementation allowed)

- Serum sodium ≥ 130 mEq/L

- Serum albumin ≥ 3 g/dL

- Elevated alkaline phosphatase or gamma-glutamyl-transferase due to bone metastasis or
liver metastasis allowed

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective double-method (including barrier) contraception
during and for 3 months after completion of study treatment

- QTc < 460 ms

- No evidence of significant active infection (e.g., pneumonia, cellulitis, or wound
abscess)

- No impaired cardiac function, including any of the following:

- Complete left bundle branch block or use of a permanent cardiac pacemaker

- Congenital long QT syndrome

- History or presence of ventricular tachyarrhythmias

- Clinically significant resting bradycardia (< 50 beats per minute)

- QTcF > 470 msec on screening ECG

- Right bundle branch block plus left anterior hemiblock (bifascicular block)

- Atrial fibrillation (ventricular heart rate > 100 beats per minute)

- Angina pectoris or acute myocardial infarction within the past 6 months

- New York Heart Association class III-IV congestive heart failure

- LVEF < 50% on baseline MUGA or ECHO

- No history of seizures

PRIOR CONCURRENT THERAPY:

- No prior cumulative anthracycline dose > 300 mg/m² of doxorubicin hydrochloride or >
480 mg/m² of epirubicin hydrochloride

- More than 5 days since prior valproic acid

- More than 3 weeks since prior and no other concurrent chemotherapy, hormonal therapy,
radiotherapy, or experimental anticancer therapy for the primary disease

- No other concurrent HDAC inhibitors

- No concurrent medications that may induce torsades de pointes or cause QTc
prolongation

- No other concurrent investigational or anticancer therapy

- No concurrent CYP3A4 inhibitors (including grapefruit or grapefruit juice) and/or
CYP3A4 inducers

- No concurrent anti-arrhythmic therapy