Panobinostat and Epirubicin in Treating Patients With Metastatic Malignant Solid Tumors

University of California San Francisco (UCSF)

Status and phase

Completed

Phase 1

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Treatments

Genetic: protein expression analysis

Drug: panobinostat

Drug: epirubicin hydrochloride

Genetic: gene expression analysis

Other: immunologic technique

Genetic: western blotting

Other: laboratory biomarker analysis

Other: pharmacological study

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00878904

UCSF-09991

NOVARTIS-CLBH589C

CDR0000639080

Details and patient eligibility

About

RATIONALE: Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as epirubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving panobinostat together with epirubicin may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of panobinostat when given together with epirubicin in treating patients with metastatic malignant solid tumors.

Full description

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.

Enrollment

40 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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