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Vorinostat and Doxorubicin in Treating Patients With Metastatic or Locally Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT00331955
Recruitment Status : Completed
First Posted : May 31, 2006
Last Update Posted : July 2, 2013
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE May 30, 2006
First Posted Date  ICMJE May 31, 2006
Last Update Posted Date July 2, 2013
Study Start Date  ICMJE March 2006
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 22, 2013)
  • Safety and tolerability as assessed by NCI CTCAE v3.0 [ Time Frame: Up to 30 days after completion of treatment ]
  • Maximum tolerated dose (MTD) of vorinostat as assessed by NCI CTCAE v3.0 [ Time Frame: 28 days ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00331955 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2013)
  • Effects of vorinostat on histone acetylation [ Time Frame: At baseline and at day 3 prior ]
  • Correlation of dose and response with biological markers for histone acetylation, Topo II expression, assays for comet moments and expression patterns of chromatin structural proteins dose [ Time Frame: Up to 30 days after completion of study treatment ]
    Our initial analysis of efficacy will be descriptive and exploratory with the goal of discerning trends in various response endpoints and correlation with biological markers.
  • Response rate (CR and PR) and clinical benefits rate (CR, PR, and stable disease) according to RECIST [ Time Frame: Up to 30 days after completion of study treatment ]
    Our initial analysis of efficacy will be descriptive and exploratory with the goal of discerning trends in various response endpoints and correlation with biological markers.
  • Duration of response (overall response, complete response, and stable disease) [ Time Frame: Up to 30 days after completion of study treatment ]
    Using Cox regression with dose as an independent variable.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vorinostat and Doxorubicin in Treating Patients With Metastatic or Locally Advanced Solid Tumors
Official Title  ICMJE Phase I Trial of Vorinostat (NSC-701852, Suberoylanilide Hydroxamic Acid) and Doxorubicin (NSC-123127, Adriamycin)
Brief Summary This phase I trial is studying the side effects and best dose of vorinostat when given together with doxorubicin in treating patients with metastatic or locally advanced solid tumors. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may help doxorubicin work better by making tumor cells more sensitive to the drug.
Detailed Description

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of vorinostat (SAHA) and doxorubicin hydrochloride in patients with metastatic or locally advanced solid tumors.

II. Determine the maximum tolerated dose of vorinostat when administered with doxorubicin hydrochloride in patients treated with this regimen.

SECONDARY OBJECTIVES:

I. Determine the response rate (complete response [CR] and partial response [PR]) and clinical benefits rate (CR, PR, and stable disease > 12 weeks) in patients treated with this regimen.

II. Determine the pharmacokinetics and pharmacodynamics of vorinostat and doxorubicin hydrochloride and their interaction.

III. Determine the effects of vorinostat on histone acetylation in peripheral blood mononuclear cells and tumors.

IV. Determine the effects of vorinostat on DNA damage induced by doxorubicin hydrochloride as a function of topoisomerase II expression.

V. Determine the effects of vorinostat on genes and proteins crucial for the maintenance of chromatin structure.

OUTLINE: This is a non-randomized, open-label, dose-escalation study of vorinostat.

Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.

Cohorts of 3-6 patients receive escalating doses of vorinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to15 patients are treated at the MTD. Mandatory biopsies are required in these patients. Patients undergo blood collection and tumor biopsies periodically during the study for pharmacologic, pharmacokinetic, pharmacodynamic, and biomarker correlative studies.

After completion of study treatment, patients are followed for at least 30 days.

PROJECTED ACCRUAL: A total of 40 patients will be accrued to this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Unspecified Adult Solid Tumor, Protocol Specific
Intervention  ICMJE
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • ADM
    • ADR
    • Adria
    • Adriamycin PFS
    • Adriamycin RDF
  • Drug: vorinostat
    Given orally
    Other Names:
    • L-001079038
    • SAHA
    • suberoylanilide hydroxamic acid
    • Zolinza
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
Study Arms  ICMJE Experimental: Treatment (vorinostat, doxorubicin hydrochloride)
Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.
Interventions:
  • Drug: doxorubicin hydrochloride
  • Drug: vorinostat
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2006)
40
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed solid tumor malignancies for which no curative therapy exists
  • Measurable or evaluable disease with tumor that is accessible to biopsy as determined by CT scan or ultrasound
  • Skin, lymph nodes, or chest wall lesions are allowed provided measurements are confirmed by 2 independent health care professionals
  • No uncontrolled CNS metastases

    • Patients with stable CNS metastases (either surgically resected, treated with gamma knife, or stable for 3 months after whole-brain radiotherapy and documented by MRI within the past 4 weeks) are eligible
  • Willing to undergo pre- and post-vorinostat tumor biopsies
  • Life expectancy ≥ 3 months
  • ECOG performance status 0-2
  • WBC > 3,000/mm^3
  • Absolute neutrophil count > 1,500/mm^3
  • Hemoglobin > 9.0 g/dL
  • Platelet count > 100,000/mm^3 (transfusion independent)
  • Creatinine ≤ 2.0 mg/mL
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 1.5 times ULN
  • LVEF > 50%
  • Fertile patients must use effective contraception during and for 6 months after completion of study treatment
  • Negative pregnancy test
  • Not pregnant or nursing
  • No significant active infection (e.g., pneumonia, cellulitis, or wound abscess)
  • No history of cardiac failure
  • No history of long QT syndrome (QTc > 470 msec)
  • No history of ventricular tachycardia or fibrillation
  • No history of seizures
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to vorinostat or other agents used in the study
  • More than 3 weeks since prior chemotherapy or radiotherapy (2 weeks for weekly regimens)
  • More than 2 weeks since prior valproic acid or any other histone deacetylase inhibitors
  • No prior anthracycline exposure
  • No other concurrent chemotherapy
  • No concurrent hormonal therapy except for maintenance therapy with luteinizing-hormone releasing-hormone agonists
  • No concurrent antiarrhythmics
  • No concurrent steroids to control brain metastasis
  • No concurrent colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) during the first course of study treatment
  • No other concurrent investigational agents for primary disease
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00331955
Other Study ID Numbers  ICMJE NCI-2012-02695
MCC 14193
CDR0000471997
NCI-6970
MCC-IRB-103476
R21CA112913 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Robert Wenham H. Lee Moffitt Cancer Center and Research Institute
PRS Account National Cancer Institute (NCI)
Verification Date July 2013

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