A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies
I. Determine the maximum tolerated dose of PXD101 (belinostat) when given in combination
with azacitidine (when azacitidine is utilized at a dose range where its effects on cellular
differentiation are known to be predominant) in patients with advanced hematologic cancers
or other diseases.
I. Identify any additive or synergistic effects of this regimen on pharmacodynamic
parameters, including apoptosis and re-expression of specific target genes.
II. Assess any evidence of clinical activity (complete remission, partial remission,
hematologic improvement, stable disease) of this regimen in these patients.
OUTLINE: This is a dose-escalation study of belinostat followed by a randomized study.
Patients receive azacitidine subcutaneously (SC) and belinostat intravenously (IV) over 30
minutes on days 1-5. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding
that at which 2 of 6 patients experience dose-limiting toxicity. After the MTD is
determined, additional patients with myelodysplastic syndromes (MDS) or acute myeloid
leukemia (with trilineage dysplasia or arising from MDS) are randomized to 1 of 2 treatment
Arm I: Patients receive azacitidine SC on days 1-5.
Arm II: Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30
minutes on days 1-5.
In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. After receiving one course, patients randomized to arm I may
crossover to receive treatment on arm II.
For patients enrolled in the randomized portion of the study, bone marrow aspirates are
obtained at baseline, and after course 1 for correlative studies. Samples are examined by
gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and apoptosis by
RT-PCR and flow cytometry. Pharmacodynamic assays are also performed.
After completion of study treatment, patients are followed periodically for up to 2 years.
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of belinostat in combination with azacitidine
Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0.
Course 1 (28 days)
University of Chicago Comprehensive Cancer Center
United States: Food and Drug Administration
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|
|University of Chicago Comprehensive Cancer Center||Chicago, Illinois 60637-1470|