Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
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.
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Acute Promyelocytic Leukemia (M3)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Refractory Anemia With Excess Blasts
Refractory Anemia With Excess Blasts in Transformation
Refractory Anemia With Ringed Sideroblasts
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
Other: laboratory biomarker analysis
Other: pharmacological study
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1/2 Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)|
- 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)3.0 (Phase I) [ Time Frame: Up to 1 month post-treatment ] [ Designated as safety issue: Yes ]Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.
- Objective overall response proportion (complete response [CR] + CR with incomplete blood count + partial response) (Phase II) [ Time Frame: Up to day 168 ] [ Designated as safety issue: No ]Ninety-five percent confidence intervals will be estimated for the response proportion in all three treatment groups via binomial proportions.
- Distribution of toxicities in the 12th treatment arm (Phase II) [ Time Frame: Up to 1 month post-treatment ] [ Designated as safety issue: Yes ]The frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE v. 3.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.
- Time to response [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
- Time to leukemic transformation [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
- Frequency of leukemic transformation [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
- Progression-free survival [ Time Frame: Time from first treatment day until objective or symptomatic progression, assessed up to 8 years ] [ Designated as safety issue: No ]Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
- Overall survival [ Time Frame: Time from first treatment day until death, assessed up to 8 years ] [ Designated as safety issue: No ]Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
|Study Start Date:||November 2006|
|Estimated Primary Completion Date:||November 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (azacitidine, vorinostat)
Patients receive azacitidine SC QD on days 1-7 and vorinostat 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.
Other Names:Drug: vorinostat
Other Names:Other: laboratory biomarker analysis
Correlative studiesOther: pharmacological study
Other Name: pharmacological studies
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00392353
|United States, Illinois|
|University of Chicago|
|Chicago, Illinois, United States, 60637|
|United States, Maryland|
|University of Maryland/Greenebaum Cancer Center|
|Baltimore, Maryland, United States, 21201|
|United States, New York|
|Albert Einstein College of Medicine|
|Bronx, New York, United States, 10461|
|Montefiore Medical Center - Moses Campus|
|Bronx, New York, United States, 10467-2490|
|North Shore University Hospital|
|Manhasset, New York, United States, 11030|
|Icahn School of Medicine at Mount Sinai|
|New York, New York, United States, 10029|
|Mount Sinai Medical Center|
|New York, New York, United States, 10029|
|Weill Medical College of Cornell University|
|New York, New York, United States, 10065|
|Principal Investigator:||Lewis Silverman||Montefiore Medical Center - Moses Campus|