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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD, defined as dose in which fewer than 1/3 or 2/6 patients experience DLT
Ohio State University
United States: Food and Drug Administration
|Ohio State University Medical Center||Columbus, Ohio 43210|