Panobinostat and Epirubicin in Treating Patients With Metastatic Malignant Solid Tumors

March 21, 2017 updated by: University of California, San Francisco

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143-1711
        • UCSF Helen Diller Family Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 120 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Response as assessed by RECIST criteria
Time Frame: 30 post end of study drug estimated to be ~24 weeks
30 post end of study drug estimated to be ~24 weeks
Progression as assessed by RECIST criteria
Time Frame: 30 post end of study drug estimated to be ~24 weeks
30 post end of study drug estimated to be ~24 weeks
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
30 post end of study drug estimated to be ~24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Pamela N. Munster, MD, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 13, 2009

Primary Completion (Actual)

May 1, 2013

Study Completion (Actual)

October 10, 2016

Study Registration Dates

First Submitted

April 8, 2009

First Submitted That Met QC Criteria

April 8, 2009

First Posted (Estimate)

April 9, 2009

Study Record Updates

Last Update Posted (Actual)

March 24, 2017

Last Update Submitted That Met QC Criteria

March 21, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000639080
  • UCSF-09991
  • NOVARTIS-CLBH589C

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Unspecified Adult Solid Tumor, Protocol Specific

Clinical Trials on gene expression analysis

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Saudi Arabia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe