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Panobinostat and Epirubicin in Treating Patients With Metastatic Malignant Solid Tumors

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00878904
First received: April 8, 2009
Last updated: October 16, 2013
Last verified: October 2013

April 8, 2009
October 16, 2013
June 2009
May 2013   (final data collection date for primary outcome measure)
  • Response as assessed by RECIST criteria [ Time Frame: 30 post end of study drug estimated to be ~24 weeks ] [ Designated as safety issue: No ]
  • Progression as assessed by RECIST criteria [ Time Frame: 30 post end of study drug estimated to be ~24 weeks ] [ Designated as safety issue: No ]
  • Adverse events and other symptoms as assessed by NCI CTCAE v3.0 [ Time Frame: 30 post end of study drug estimated to be ~24 weeks ] [ Designated as safety issue: Yes ]
  • Response as assessed by RECIST criteria [ Designated as safety issue: No ]
  • Progression as assessed by RECIST criteria [ Designated as safety issue: No ]
  • Adverse events and other symptoms as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00878904 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Panobinostat and Epirubicin in Treating Patients With Metastatic Malignant Solid Tumors
A Phase I Trial of Panobinostat (LBH589) and Epirubicin in Patients With Solid Tumor Malignancies

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.

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.

Interventional
Phase 1
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Unspecified Adult Solid Tumor, Protocol Specific
  • 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
Experimental: treatment with Panobinostat and Epirubicin
Interventions:
  • 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
40
December 2014
May 2013   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00878904
CDR0000639080, UCSF-09991, NOVARTIS-CLBH589C
Yes
University of California, San Francisco
University of California, San Francisco
National Cancer Institute (NCI)
Principal Investigator: Pamela N. Munster, MD University of California, San Francisco
University of California, San Francisco
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP