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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Non-Small Cell Lung Cancer

Conditions
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Recurrent Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: decitabine
* Drug: valproic acid
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (decitabine, valproic acid)<br>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<br>* Given IV<br>* Other names: DAC;Drug: valproic acid<br>* Given PO<br>* Other names: VA;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD, defined as dose in which fewer than 1/3 or 2/6 patients experience DLT |  | 28 days |