Panobinostat and Epirubicin in Treating Patients With Metastatic Malignant Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: epirubicin hydrochloride
* Drug: panobinostat
* Genetic: gene expression analysis
* Genetic: protein expression analysis
* Genetic: western blotting
* Other: immunologic technique
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment with Panobinostat and Epirubicin<br> | Drug: epirubicin hydrochloride<br> <br> Drug: panobinostat<br> <br> Genetic: gene expression analysis<br> <br> Genetic: protein expression analysis<br> <br> Genetic: western blotting<br> <br> Other: immunologic technique<br> <br> Other: laboratory biomarker analysis<br> <br> Other: pharmacological study<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response as assessed by RECIST criteria |  | 30 post end of study drug estimated to be  24 weeks | 
| Progression as assessed by RECIST criteria |  | 30 post end of study drug estimated to be  24 weeks | 
| Adverse events and other symptoms as assessed by NCI CTCAE v3.0 |  | 30 post end of study drug estimated to be  24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific