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

May 1, 2013 updated by: National Cancer Institute (NCI)

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, Myelodysplasias and Myeloproliferative Disorders

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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 courses in the absence of disease progression or unacceptable toxicity.

Patients who achieve complete response after 1 course of therapy may receive 1 or 2 more courses of therapy. Patients who achieve partial response after 1 course of therapy may receive 1 more course of therapy. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 10 patients are treated at that dose. Blood, buccal cells, and bone marrow samples are collected prior to and during treatment. Samples are used for pharmacokinetic and pharmacodynamic studies, protein expression studies, and gene expression profiling. After completion of study treatment, patients are followed within 30 days.

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21201-1595
        • University of Maryland Greenebaum Cancer Center
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • University of Pittsburgh

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of 1 of the following:

    • Relapsed or refractory acute myeloid leukemia (AML)

      • Patients with acute promyelocytic leukemia t(15;17) must have failed prior tretinoin and arsenic trioxide-containing regimen

        • Must be refractory to both agents with absence of durable hematologic response OR relapsed after a complete response duration of < 6 months
    • Relapsed or refractory acute lymphoblastic leukemia

    • Chronic myelogenous leukemia in accelerated or blastic phase

      • Must be refractory to treatment with imatinib mesylate or dasatinib

        • Disease progression despite continued treatment with imatinib mesylate or dasatinib
      • Patients in accelerated or blastic phase are eligible if unable to tolerate imatinib mesylate provided their disease has progressed on dasatinib or if unable to tolerate dasatinib
    • AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or myeloproliferative disorders (MPD)
    • Secondary or therapy-related AML
  • No active CNS leukemia
  • Leukostasis OR leukemic blast count > 50,000/mm³ allowed provided patient is treated with emergency leukapheresis or hydroxyurea to reduce leukemic blast count to < 30,000/mm³
  • ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • Creatinine ≤ 2.0 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No history of cytarabine-related neurotoxicity
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in the study

  • No other uncontrolled illness, including, but not limited to, any of the following:

    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness or social situation that would preclude compliance with study requirements
  • Infection allowed provided patient is receiving active treatment
  • No HIV positivity
  • See Disease Characteristics

  • Recovered from prior therapy

    • Persistent alopecia, fingernail discoloration, or hematologic abnormalities (primarily related to underlying disease) > 4 weeks after last course of chemotherapy or radiotherapy does not exclude patient
  • At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor

  • No more than 3 prior courses of induction/reinduction chemotherapy, including induction and consolidation therapy or induction therapy after any bone marrow transplantation or similar procedure

    • Prior low-dose azacitidine, growth factors, cytokines, thalidomide, interferon, or imatinib mesylate for treatment of preceding MDS/MPD do not count as prior induction/reinduction therapy
  • At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas [e.g., carmustine] or mitomycin C) or radiotherapy
  • At least 24 hours since prior hydroxyurea
  • At least 2 weeks since prior imatinib mesylate, hematopoietic growth factors, and biological agents
  • At least 4 weeks since prior autologous stem cell transplantation

  • Prior allogeneic stem cell transplantation allowed if all of the following criteria are met:

    • At least 90 days since prior transplant
    • No evidence of graft-vs-host disease
    • At least 2 weeks since prior immunosuppressive therapy
  • No other concurrent anticancer agents or therapies
  • No other concurrent investigational agents
  • Concurrent hydroxyurea or leukapheresis allowed on days 1-10 of study treatment to control rising leukemic blasts (blasts > 30,000/mm³) or leukostasis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine 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 courses in the absence of disease progression or unacceptable toxicity.
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Drug: vorinostat
Given orally
Other Names:
  • SAHA
  • Zolinza
  • L-001079038
  • suberoylanilide hydroxamic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Course 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline, day 4-7 of course 1, and after each course
Progression-free survival
Time Frame: At 30 days after completion of study treatment and continued follow up visits
Estimated using the Kaplan-Meir method.
At 30 days after completion of study treatment and continued follow up visits
Disease-specific survival
Time Frame: At 30 days after completion of study treatment and continued follow up visits
Estimated using the Kaplan-Meir method.
At 30 days after completion of study treatment and continued follow up visits
One-year survival
Time Frame: At 1 year
Estimated using the Kaplan-Meir method.
At 1 year
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.
At 30 days after completion of study treatment and continued follow up visits
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.
Baseline and days 4-7 of course 1
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.
Baseline and days 4-7 of course 1
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.
Baseline and days 4-7 of course 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Douglas Ross, University of Maryland Greenebaum Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2006

Primary Completion (Actual)

November 1, 2011

Study Registration Dates

First Submitted

July 26, 2006

First Submitted That Met QC Criteria

July 26, 2006

First Posted (Estimate)

July 27, 2006

Study Record Updates

Last Update Posted (Estimate)

May 3, 2013

Last Update Submitted That Met QC Criteria

May 1, 2013

Last Verified

May 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00088
  • GCC 0447
  • NCI-6829
  • CDR0000487484

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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