Clinical Trial: Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination With Cytosine Arabinoside (Ara-C) and Etoposide for Patients With Relapsed and/or Refractory Acute Leukemias, Myel

Brief Summary: This phase I trial is studying the side effects and best dose of vorinostat when given together with cytarabine and etoposide in treating patients with relapsed or refractory acute leukemia or myelodysplastic syndromes or myeloproliferative disorders. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with cytarabine and etoposide may kill more cancer cells.

Detailed Summary:

OBJECTIVES:

I. Determine the feasibility, tolerability, and toxicities, in terms of the maximum tolerated dose (MTD), of the sequential combination of vorinostat (SAHA) followed by cytarabine and etoposide in patients with relapsed and/or refractory acute leukemia or transforming myelodysplastic syndromes or myeloproliferative disorders.

II. Determine whether the addition of SAHA to cytarabine and etoposide chemotherapy improves outcome, in terms of complete response rate, duration of response, and overall survival, in these patients.

III. Determine the effects of SAHA on induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors DR4 and DR5 and other pro-apoptotic mediators in patient-derived cancer cells (leukemia blast cells) and somatic cells (buccal mucosa cells, using pre-SAHA and on SAHA treatment samples).

IV. Determine the ability of SAHA to block leukemia blast cells in the G1 phase of the cell cycle (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).

V. Determine the effects of SAHA on the expression of P-glycoprotein/MDR1/ABCB1, and the breast cancer resistance protein (BCRP/ABCG2), using functional and mRNA/protein assays for these transporters (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).

OUTLINE: This is a dose-escalation study of vorinostat (SAHA).

Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine intravenously (IV) over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 cours
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide [ Time Frame: Course 1 ]

Based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.


Original Primary Outcome:

Current Secondary Outcome:

  • Response rate [ Time Frame: Baseline, day 4-7 of course 1, and after each course ]
    Measured using a bone marrow aspirate and/or biopsy. 90% confidence interval will be calculated
  • Progression-free survival [ Time Frame: At 30 days after completion of study treatment and continued follow up visits ]
    Estimated using the Kaplan-Meir method.
  • Disease-specific survival [ Time Frame: At 30 days after completion of study treatment and continued follow up visits ]
    Estimated using the Kaplan-Meir method.
  • One-year survival [ Time Frame: At 1 year ]
    Estimated using the Kaplan-Meir method.
  • Overall survival [ Time Frame: At 30 days after completion of study treatment and continued follow up visits ]
    Measured from time of enrollment onto this study to the time of death. Estimated using the Kaplan-Meir method.
  • Degree of upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors and proteins associated with apoptosis [ Time Frame: Baseline and days 4-7 of course 1 ]
    Performed by the Rnase protection assay.
  • Alterations in cell cycle phase [ Time Frame: Baseline and days 4-7 of course 1 ]
    Patient-derived bone marrow or peripheral blood mononuclear cells will be evaluated for cell cycle phase distribution, using the hypotonic propidium-iodide method and flow cytometry.
  • Expression of MDR proteins at MTD of SAHA [ Time Frame: Baseline and days 4-7 of course 1 ]
    Using quantitative, real-time polymerase chain reaction (PCR) methods with product detected using specific hybridization probes.


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: July 26, 2006
Date Started: May 2006
Date Completion:
Last Updated: May 1, 2013
Last Verified: May 2013