A Phase I Trial of Panobinostat (LBH589) and Epirubicin in Patients With Solid Tumor Malignancies

Inclusion Criteria

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