Clinical Trial: Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: A Phase 1/2 Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)

Brief Summary: 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.

Detailed Summary:

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
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Distribution of toxicities in the 12th treatment arm (Phase II) [ Time Frame: Up to 1 month post-treatment ]
    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.
  • 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 ]
    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 ]
    Ninety-five percent confidence intervals will be estimated for the response proportion in all three treatment groups via binomial proportions.


Original Primary Outcome:

Current Secondary Outcome:

  • Frequency of leukemic transformation [ Time Frame: Up to day 84 ]
  • Overall survival [ Time Frame: Time from first treatment day until death, assessed up to 8 years ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
  • Progression-free survival [ Time Frame: Time from first treatment day until objective or symptomatic progression, assessed up to 8 years ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
  • Time to leukemic transformation [ Time Frame: Up to day 84 ]
  • Time to response [ Time Frame: Up to day 84 ]


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: October 25, 2006
Date Started: November 2006
Date Completion:
Last Updated: May 23, 2017
Last Verified: May 2017