Vorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes

September 27, 2013 updated by: National Cancer Institute (NCI)

A Phase 1 Study of Suberoylanilide Hydroxamic Acid (Vorinostat, SAHA) in Combination With Idarubicin in Relapsed or Refractory Leukemia

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

Study Overview

Detailed Description

OBJECTIVES:

I. Determine the maximum tolerated dose and dose-limiting toxicities of vorinostat (SAHA) in combination with standard-dose idarubicin in patients with relapsed or refractory acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, acute promyelocytic leukemia, or chronic myelogenous leukemia in blastic phase.

II. Describe the clinical activity of this regimen in these patients. III. Determine the in vivo molecular effects of this regimen, including the effects on DNA topoisomerase IIα mRNA expression and on the induction of γH2AX, histone H3 and H4 acetylation, as well as changes in the gene expression profile.

IV. Determine the pharmacokinetic characteristics of this regimen in these patients.

OUTLINE:

This is a randomized, dose-escalation study of vorinostat (SAHA). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral SAHA three times daily on days 1-14 and idarubicin IV over 15 minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.*

ARM II: Patients receive oral SAHA three times daily and idarubicin IV over 15 minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.*

Note: *Patients completing 6 courses of therapy or who reach the maximum cumulative dose of idarubicin or an equivalent anthracycline and achieve clinical benefit may continue treatment with SAHA alone 3 times daily on days 1-14 of each course, in the absence of disease progression or unacceptable toxicity.

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 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity. An additional 10 patients are treated at the MTD.

Patients undergo blood collection and bone marrow biopsies periodically during the study for pharmacologic, biomarker, and genetic studies.

After completion of study treatment, patients are followed at 4 weeks and then periodically thereafter.

Study Type

Interventional

Enrollment (Actual)

40

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

    • Texas
      • Houston, Texas, United States, 77030
        • M D Anderson Cancer Center

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

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed relapsed/refractory acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome or blastic phase chronic myelogenous leukemia.
  • Patients that have received cumulative doses (or its equivalent to other anthracycline) of more than 290 mg/m^2 of idarubicin will be excluded from the study. No other limitations in terms of number of prior therapies or type of therapies apply to this study.
  • ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
  • Total bilirubin ≤ 2 mg/dL
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 2 mg/dL
  • LVEF ≥ 50%
  • Not nursing or pregnant
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • At least 2 weeks since prior chemotherapy and recovered, unless there is evidence of rapidly progressive disease, at least 24 hours since prior hydroxyurea for rapidly proliferating disease
  • At least 2 weeks since prior imatinib mesylate
  • At least 2 weeks since prior histone deacetylase inhibitors, including valproic acid
  • Maximum cumulative dose of prior idarubicin or equivalent anthracycline drug ≤ 290 mg/m2
  • No concurrent epoetin alfa or hematopoietic colony-stimulating factors during the first course of study therapy
  • No concurrent prophylactic hematopoietic colony-stimulating factors
  • Myelodysplastic syndromes requiring treatment, previously treated with either azacytidine or decitabine, unless it was contraindicated; blastic phase chronic myelogenous leukemia; failed prior imatinib mesylate-based therapy
  • Patients with MDS should have received therapy with either 5-azacytidine or 5-aza-2'-deoxycytidine, unless the patient had a contraindication to such therapy, and should require therapy.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients with clinical evidence of CNS disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • No unstable angina pectoris
  • Considered ineligible for or refused potentially curative therapy, including allogeneic stem cell transplantation, with or without standard induction therapy
  • No history of allergic reaction attributed to compounds of similar chemical or biological composition to vorinostat (SAHA) or other agents used in this study
  • No ongoing or active infection
  • No symptomatic congestive heart failure
  • No cardiac arrhythmia
  • No other uncontrolled illness
  • No psychiatric illness or social situation that would preclude study compliance
  • No other concurrent investigational agents
  • No other concurrent anticancer agents or therapies
  • No concurrent combination antiretroviral therapy for HIV-positive patients

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm I (vorinostat, idarubicin)
Patients receive oral SAHA three times daily on days 1-14 and idarubicin IV over 15 minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients completing 6 courses of therapy or who reach the maximum cumulative dose of idarubicin or an equivalent anthracycline and achieve clinical benefit may continue treatment with SAHA alone 3 times daily on days 1-14 of each course, in the absence of disease progression or unacceptable toxicity.
Correlative studies
Correlative studies
Other Names:
  • pharmacological studies
Given orally
Other Names:
  • SAHA
  • Zolinza
  • L-001079038
  • suberoylanilide hydroxamic acid
Given IV
Other Names:
  • IDA
  • 4-demethoxydaunorubicin
  • 4-DMDR
  • DMDR
Active Comparator: Arm II (vorinostat, idarubicin)
Patients receive oral SAHA three times daily and idarubicin IV over 15 minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients completing 6 courses of therapy or who reach the maximum cumulative dose of idarubicin or an equivalent anthracycline and achieve clinical benefit may continue treatment with SAHA alone 3 times daily on days 1-14 of each course, in the absence of disease progression or unacceptable toxicity.
Correlative studies
Correlative studies
Other Names:
  • pharmacological studies
Given orally
Other Names:
  • SAHA
  • Zolinza
  • L-001079038
  • suberoylanilide hydroxamic acid
Given IV
Other Names:
  • IDA
  • 4-demethoxydaunorubicin
  • 4-DMDR
  • DMDR

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Maximum-tolerated dose (MTD) of vorinostat determined by dose-limiting toxicities (DLT) as measured by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.3.0
Time Frame: 21 days
21 days

Collaborators and Investigators

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

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

March 1, 2006

Primary Completion (Actual)

January 1, 2010

Study Registration Dates

First Submitted

May 30, 2006

First Submitted That Met QC Criteria

May 30, 2006

First Posted (Estimate)

May 31, 2006

Study Record Updates

Last Update Posted (Estimate)

September 30, 2013

Last Update Submitted That Met QC Criteria

September 27, 2013

Last Verified

September 1, 2013

More Information

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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