Decitabine, Vorinostat, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01130506
First received: May 25, 2010
Last updated: September 16, 2014
Last verified: June 2014
  Purpose

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


Condition Intervention Phase
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
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)
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Drug: decitabine
Drug: vorinostat
Drug: cytarabine
Other: pharmacological study
Other: diagnostic laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Decitabine, Vorinostat, and Cytarabine in Acute Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD of decitabine and vorinostat, determined according to incidence of DLT graded using NCI CTCAE version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Toxicity, graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Overall response rate, assessed using International Working Group criteria [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]

Enrollment: 17
Study Start Date: May 2010
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, cytarabine, decitabine)

INDUCTION THERAPY: Patients receive decitabine IV over 1 hour on days 1-10; oral vorinostat on days 5-10; and high-dose cytarabine IV over 2 hours on days 12, 14, and 16 in the absence of disease progression or unacceptable toxicity. Patients who achieve CR proceed to maintenance therapy. Patients who achieve CR with incomplete blood count recovery undergo bone marrow aspiration and biopsy at count recovery or day 42 before proceeding to maintenance therapy.

MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and oral vorinostat on days 5-10. Treatment repeats every 28 days for up to 11 courses in the absence of disease progression or unacceptable toxicity.

Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: diagnostic laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of decitabine, vorinostat, and cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML) and select subsets of high risk leukemia/myelodysplastic syndromes (MDS).

II. To define the specific toxicities and the dose limiting toxicity (DLT) of the combination.

SECONDARY OBJECTIVES:

I. To develop a platform for specifically targeting MLL PTD, for future efficacy studies.

II. To determine the overall response rate (ORR) of this regimen in relapsed/ refractory AML.

III. To examine the role of decitabine and vorinostat in re-expression of MLL- WT in patients with MLL PTD via correlative studies specific to patients with MLL PTD and the preliminary relationship of this to clinical response in patients with MLL PTD+ AML.

IV. To correlate the biological activity of decitabine as demethylating agent (changes in target gene methylation and gene expression, DNMT1 protein expression, global methylation) with clinical endpoints V. To explore the biologic role of microRNAs in determining clinical response to the combination and achievement of the other pharmacodynamic endpoints.

OUTLINE: This is a dose-escalation study of cytarabine.

INDUCTION THERAPY: Patients receive decitabine IV over 1 hour on days 1-10; oral vorinostat on days 5-10; and high-dose cytarabine IV over 2 hours on days 12, 14, and 16 in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) proceed to maintenance therapy. Patients who achieve CR with incomplete blood count recovery undergo bone marrow aspiration and biopsy at count recovery or day 42 before proceeding to maintenance therapy.

MAINTENANCE THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and oral vorinostat on days 5-10. Treatment repeats every 28 days for up to 11 courses in the absence of disease progression or unacceptable toxicity.

Blood samples and additional bone marrow aspirate and biopsy are collected at baseline and during study for re-expression of mixed lineage leukemia-wild-type, changes in target gene methylation and gene expression, DNMT1 protein expression, global methylation, and other pharmacodynamic studies.

After completion of study therapy, patients are followed up for 30 days.

  Eligibility

Ages Eligible for Study:   18 Years to 59 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of acute myeloid leukemia (AML)

    • Relapsed or refractory disease

      • Secondary AML or therapy related disease (t-AML) allowed
      • AML with mixed-lineage leukemia partial-tandem duplication (MLL PTD)
  • No advanced malignant solid tumors or additional active hematologic malignancies
  • No active CNS disease or granulocytic sarcoma as sole site of disease
  • ECOG performance status 0-2
  • Life expectancy > 6 months (for patients with co-morbid medical illness)
  • Total bilirubin < 2.0 mg/dL
  • AST and/or ALT 2.5 times upper limit of normal
  • Creatinine < 2.0 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must agree to use effective contraception before and during study therapy
  • Known HIV infection allowed provided the following criteria are met:

    • No history of AIDS
    • High CD4 cell count (> 400/mm^3)
    • Low HIV viral load (< 30,000 copies/mL plasma)
    • No requirement for anti-HIV therapy
  • No history of medically serious allergic reactions attributed to decitabine, vorinostat, or cytarabine, or compounds of similar chemical or biologic composition that are not easily managed
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Serious cardiac arrhythmia
    • Psychiatric illness or social situations that would limit compliance with study requirements
    • Myocardial infarction within the past 6 months
    • NYHA class III-IV heart failure
    • Severe uncontrolled ventricular arrhythmias
    • Electrocardiographic evidence of acute ischemia or active conduction system abnormalities
    • Medical comorbidities that would preclude safety evaluation of the combination therapy
  • No serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • No history of neurologic toxicity attributed to cytarabine or vorinostat
  • Active infection that is under control allowed

    • Patients with uncontrolled infection shall not be enrolled until it is treated and brought under control
  • Able to swallow pills
  • Prior decitabine or azacitidine for myelodysplastic syndrome or AML allowed
  • Prior high-dose cytarabine (> 1 g/m²/dose) allowed
  • More than 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy and recovered to toxicities < grade 2
  • More than 2 weeks since valproic acid or any other histone deacetylase inhibitor
  • More than 14 days since prior and no other concurrent investigational agents
  • No concurrent anti-HIV therapy
  • No concurrent warfarin or Coumadin® derivative
  • No other concurrent anticancer agents or therapies
  • No concurrent palliative radiotherapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01130506

Locations
United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: William Blum Ohio State University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01130506     History of Changes
Other Study ID Numbers: NCI-2011-01488, NCI-2011-01488, 2010C0009, CDR0000673876, 09150, 8485, P30CA016058, U01CA076576
Study First Received: May 25, 2010
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Decitabine
Vorinostat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Histone Deacetylase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 18, 2014