A Phase 1 Study of Vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in Combination With Decitabine in Patients With Advanced Solid Tumors, Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia in Blast Crisis
I. Establish the maximum tolerated dose and recommended phase II dose of vorinostat in
conjunction with decitabine in patients with advanced solid tumors or relapsed or refractory
non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic
myelogenous leukemia in blast crisis.
I. Identify the minimal effective dose of vorinostat in conjunction with decitabine that
will lead to DNA demethylation, histone acetylation, and gene reactivation with tolerable
toxicity in these patients.
II. Determine the pharmacokinetic profiles of vorinostat and decitabine in these patients.
Correlate pharmacokinetic profiles of vorinostat and decitabine with toxicity and biological
activity in these patients.
III. Assess the antitumor activity of vorinostat and decitabine in these patients.
OUTLINE: This is a parallel group, multicenter, dose-escalation study of vorinostat.
Patients are stratified according to disease (solid tumors or non-Hodgkin's lymphoma [NHL]
vs hematological malignancies).
Patients receive 1 of 2 dosing regimens.
Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on
days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1
hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or
Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on
days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on
days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days
Courses repeat every 28 days or 21 days (patients with hematological malignancies only) in
the absence of disease progression or unacceptable toxicity. In both groups, cohorts of 3-6
patients receive escalating doses of vorinostat 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. The dose level just below MTD would be declared the
recommended phase II dose (RPTD). Up to 10 patients are treated at the RPTD. After
completion of study treatment, patients are followed at 4 weeks.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Princess Margaret Hospital Phase 2 Consortium
United States: Food and Drug Administration