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

Phase 1
18 Years
Open (Enrolling)
Recurrent Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

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


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.


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.

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD, defined as dose in which fewer than 1/3 or 2/6 patients experience DLT

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Gregory Otterson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

April 2004

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



Ohio State University Medical Center Columbus, Ohio  43210