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
  Purpose

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.


Condition Intervention Phase
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
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Panobinostat (LBH589) and Epirubicin in Patients With Solid Tumor Malignancies

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • 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 ]

Enrollment: 40
Study Start Date: June 2009
Estimated Study Completion Date: December 2014
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: treatment with Panobinostat and Epirubicin 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

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00878904

Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143-1711
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Pamela N. Munster, MD University of California, San Francisco
  More Information

Additional Information:
No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00878904     History of Changes
Other Study ID Numbers: CDR0000639080, UCSF-09991, NOVARTIS-CLBH589C
Study First Received: April 8, 2009
Last Updated: October 16, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
unspecified adult solid tumor, protocol specific

Additional relevant MeSH terms:
Neoplasms
Epirubicin
Panobinostat
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 20, 2014