This phase I/II trial studies the side effects and best dose of vorinostat and azacitidine and to see how well they work in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Vorinostat may stop the growth of cancer or abnormal cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer or abnormal cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with azacitidine may kill more cancer or abnormal cells.
PRIMARY OBJECTIVES: I. To evaluate the safety and toxicity of vorinostat in combination with azacitidine in patients with myelodysplastic syndromes (MDS) and some select patients with acute myeloid leukemia (AML) (step 1). II. To identify doses of both vorinostat and azacitidine for safe combination of the 2 agents that can be administered in repetitive cycles over time for use in phase II studies. III. To determine the response rate of patients treated with the combination of suberoylanilide hydroxamic acid (SAHA) (vorinostat) and azacitidine at the doses established as safe and effective in Step 1 in an expanded cohort of patients with MDS. IV. To obtain preliminary data on the effects of treatment with the combination of vorinostat and Aza C (azacitidine) in patients with MDS on a series of biologic surrogate markers including: deoxyribonucleic acid (DNA) methylation of specific genes (e.g. p15); histone acetylation; hematopoietic progenitor growth and differentiation; the fate of the MDS clone and changes in gene expression by array profiling. SECONDARY OBJECTIVES: I. Determine effect of treatment with the combination on time to response, time to leukemic transformation and frequency of transformation to leukemia in patients with MDS during the phase II segment of the study. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-7 and vorinostat orally (PO) 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed monthly for 6 months and then every 2 months thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
135
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States
North Shore University Hospital
Manhasset, New York, United States
Mount Sinai Hospital
New York, New York, United States
NYP/Weill Cornell Medical Center
New York, New York, United States
Montefiore Medical Center-Weiler Hospital
The Bronx, New York, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, United States
Incidence of toxicities of vorinostat in combination with azacitidine graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 (Phase I)
Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.
Time frame: Up to 1 month post-treatment
Objective overall response proportion (complete response [CR] + CR with incomplete blood count + partial response) (Phase II)
Ninety-five percent confidence intervals will be estimated for the response proportion in all three treatment groups via binomial proportions.
Time frame: Up to day 168
Distribution of toxicities in the 12th treatment arm (Phase II)
The frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE v. 5.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.
Time frame: Up to 1 month post-treatment
Time to response
Time frame: Up to day 84
Time to leukemic transformation
Time frame: Up to day 84
Frequency of leukemic transformation
Time frame: Up to day 84
Progression-free survival
Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Time frame: Time from first treatment day until objective or symptomatic progression, assessed up to 8 years
Overall survival
Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Time frame: Time from first treatment day until death, assessed up to 8 years
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