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Decitabine and Valproic Acid in Treating Patients With Non-Small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00084981
Recruitment Status : Completed
First Posted : June 11, 2004
Last Update Posted : September 30, 2013
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
This phase I trial is studying the side effects and best dose of decitabine and valproic acid in treating patients with non-small cell lung cancer. Drugs used in chemotherapy, such as decitabine and valproic acid, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

Condition or disease Intervention/treatment Phase
Recurrent Non-small Cell Lung Cancer Stage IV Non-small Cell Lung Cancer Drug: decitabine Drug: valproic acid Other: pharmacological study Other: laboratory biomarker analysis Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of decitabine and valproic acid in patients with non-small cell lung cancer.

II. Determine the recommended phase II dose of this regimen in these patients.

SECONDARY OBJECTIVES:

I. Determine the ability of this regimen to lead to biological changes in tumor and surrogate tissues in these patients, including hypomethylation of target genes known to be methylated in NSCLC (CDKN2, APC, BMP3B, CDH1 and RASSF1A) in biopsy specimens and surrogate tissues (peripheral blood mononuclear cells [PBMC] and plasma/serum DNA); acetylation and methylation changes in histones from tumor and surrogate tissues (PBMC and oral epithelial cells); inhibition of histone deacetylase (HDAC) activity in peripheral blood; pharmacokinetic analysis of Decitabine and Valproic Acid; DNA methyltransferase 1 (DNMT1) protein loss in PBMC and buccal cells; response of hemoglobin F in patients with non-hematologic conditions to DNMT and HDAC inhibition; and preliminary evidence of antitumor activity in non-small cell lung cancer.

OUTLINE: This is a dose-escalation study.

Patients receive decitabine IV over 1 hour on days 1-10 and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of decitabine and valproic acid 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. After the MTD is determined, an additional 6 patients are treated at that dose.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Non-Small Cell Lung Cancer
Study Start Date : April 2004
Actual Primary Completion Date : February 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (decitabine, valproic acid)

Patients receive decitabine IV over 1 hour on days 1-10 and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of decitabine and valproic acid until the 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. After the MTD is determined, an additional 6 patients are treated at that dose.

 Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC

Drug: valproic acid
Given PO
Other Names:
  • Alti-Valproic
  • Depakene
  • Novo-Valproic
  • VA

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Other: laboratory biomarker analysis
Correlative studies


Outcome Measures
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Primary Outcome Measures :
  1. MTD, defined as dose in which fewer than 1/3 or 2/6 patients experience DLT [ Time Frame: 28 days ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed non-small cell lung cancer
  • Tumor accessible to biopsy by bronchoscopy, through surface biopsy (e.g., skin punch biopsy for skin/subcutaneous metastasis) or through CT scan guidance
  • Not eligible for curative surgery, chemotherapy, radiotherapy, or multimodality treatment options

  • No uncontrolled brain metastases

    • Controlled brain metastases allowed provided patient has no neurologic deterioration when off steroids; has completed prior radiotherapy or other treatments; has fully recovered from prior treatment; and does not require anticonvulsants
  • Performance status - ECOG 0-2
  • Performance status - Karnofsky 60-100%
  • More than 12 weeks
  • Absolute neutrophil count > 1,500/mm^3
  • Platelet count > 100,000/mm^3
  • WBC > 3,000/mm^3
  • AST and ALT =< 2.5 times upper limit of normal (ULN)
  • Bilirubin =< 1.5 times ULN
  • Creatinine =< 1.5 times ULN
  • Creatinine clearance >= 60 mL/min
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No prior allergic reaction to compounds of similar chemical or biological composition to decitabine, valproic acid, or other study agents
  • No other concurrent uncontrolled illness
  • No ongoing or active infection requiring antibiotics
  • No history of seizures requiring anticonvulsants
  • No medical problem that would preclude study participation
  • No psychiatric illness or social situation that would preclude study compliance
  • No other active malignancy except non-melanoma skin cancer or carcinoma in situ of the cervix
  • No concurrent prophylactic growth factors (e.g., filgrastim [G-CSF] or epoetin alfa)
  • No more than 3 prior chemotherapy regimens
  • More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered

  • Prior definitive radiotherapy to the chest allowed

    • Clinical (radiographic or other) evidence of tumor progression for previously irradiated indicator lesion in the chest
  • More than 2 weeks since prior radiotherapy and recovered
  • No concurrent palliative radiotherapy
  • Prior curative or palliative intent surgery allowed
  • At least 2 weeks since prior surgery and recovered
  • At least 4 weeks since prior photodynamic therapy
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent anticancer agents or therapies
  • No other concurrent investigational agents

  • No concurrent administration of any of the following medications:

    • Aspirin

      • Chronic low-dose (=< 81 mg/day) aspirin allowed
    • Felbamate
    • Rifampin
    • Amitriptyline
    • Nortriptyline
    • Carbamazepine
    • Clonazepam
    • Diazepam
    • Ethosuximide
    • Lamotrigine
    • Phenobarbital
    • Barbiturates
    • Primidone
    • Phenytoin
    • Zidovudine
  • No concurrent divalproex sodium
  • Concurrent gabapentin for neuropathic pain allowed
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00084981


Locations
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United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Gregory Otterson Ohio State University
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00084981    
Other Study ID Numbers: NCI-2012-01451
NCI-2012-01451 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI-6237
OSU-2003C0087
OSU-0346
CDR0000367115
OSU 0346 ( Other Identifier: Ohio State University Medical Center )
6237 ( Other Identifier: CTEP )
U01CA076576 ( U.S. NIH Grant/Contract )
First Posted: June 11, 2004    Key Record Dates
Last Update Posted: September 30, 2013
Last Verified: September 2013
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Decitabine
Azacitidine
Valproic Acid
 Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Anticonvulsants
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs