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About
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.
Full 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.
Enrollment
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Inclusion and exclusion 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
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
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
Felbamate
Rifampin
Amitriptyline
Nortriptyline
Carbamazepine
Clonazepam
Diazepam
Ethosuximide
Lamotrigine
Phenobarbital
Barbiturates
Primidone
Phenytoin
Zidovudine
No concurrent divalproex sodium
Concurrent gabapentin for neuropathic pain allowed
Primary purpose
Allocation
Interventional model
Masking
25 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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