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Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), December 2008
Sponsors and Collaborators: University of Maryland Greenebaum Cancer Center
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00357305
  Purpose

RATIONALE: 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.

PURPOSE: 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.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Drug: cytarabine
Drug: etoposide
Drug: vorinostat
Procedure: gene expression profiling
Procedure: pharmacological study
Procedure: protein expression analysis
Phase I

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic
Drug Information available for: Cytarabine Cytarabine hydrochloride Etoposide Etoposide phosphate Suberoylanilide hydroxamic acid
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment
Official Title: A 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

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

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Response rate [ Designated as safety issue: No ]
  • Progression-free survival [ Designated as safety issue: No ]
  • Disease-specific survival [ Designated as safety issue: No ]
  • One-year survival [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Degree of upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors and proteins associated with apoptosis [ Designated as safety issue: No ]
  • Alterations in cell cycle phase [ Designated as safety issue: No ]
  • Expression of MDR proteins at MTD of SAHA [ Designated as safety issue: Yes ]

Estimated Enrollment: 25
Study Start Date: May 2006
Estimated Primary Completion Date: August 2007 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

  • 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.
  • 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.
  • 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).
  • 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).
  • 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 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.

PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • 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

PATIENT CHARACTERISTICS:

  • 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

PRIOR CONCURRENT THERAPY:

  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00357305

Locations
United States, Maryland
Greenebaum Cancer Center at University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Clinical Trials Office - Greenebaum Cancer Center at Universit     800-888-8823        
United States, Pennsylvania
UPMC Cancer Centers Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Clinical Trials Office - UPMC Cancer Centers     412-647-8073        
Sponsors and Collaborators
University of Maryland Greenebaum Cancer Center
Investigators
Study Chair: Douglas D. Ross, MD, PhD University of Maryland School of Medicine
  More Information

Clinical trial summary from the National Cancer Institute's PDQ® database  This link exits the ClinicalTrials.gov site

Study ID Numbers: CDR0000487484, MSGCC-0447, NCI-6829, MSGCC-H-27631
Study First Received: July 26, 2006
Last Updated: December 23, 2008
ClinicalTrials.gov Identifier: NCT00357305  
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
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
recurrent adult acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
adult acute promyelocytic leukemia (M3)
relapsing chronic myelogenous leukemia
atypical chronic myeloid leukemia
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
de novo myelodysplastic syndromes
adult acute minimally differentiated myeloid leukemia (M0)
adult acute myeloblastic leukemia without maturation (M1)
adult acute myeloblastic leukemia with maturation (M2)
adult acute myelomonocytic leukemia (M4)
adult acute monoblastic leukemia (M5a)
adult acute monocytic leukemia (M5b)
adult erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
adult acute megakaryoblastic leukemia (M7)
adult acute basophilic leukemia
adult acute eosinophilic leukemia
chronic myelomonocytic leukemia
chronic eosinophilic leukemia

Study placed in the following topic categories:
Polycythemia
Blast Crisis
Chronic myelogenous leukemia
Chronic myelomonocytic leukemia
Di Guglielmo's syndrome
Preleukemia
Hemorrhagic thrombocythemia
Neoplasm Metastasis
Leukemia, Promyelocytic, Acute
Thrombocythemia, Hemorrhagic
Acute myeloid leukemia, adult
Etoposide
Myelodysplastic syndromes
Essential thrombocytosis
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hematologic Diseases
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Myeloproliferative Disorders
Acute myelogenous leukemia
Acute promyelocytic leukemia
Leukemia, Myeloid
Myelodysplastic myeloproliferative disease
Leukemia, Erythroblastic, Acute
Leukemia, Myeloid, Accelerated Phase
Acute monoblastic leukemia
Leukemia, Monocytic, Acute
Leukemia, Lymphoid
Precancerous Conditions
Acute myelomonocytic leukemia

Additional relevant MeSH terms:
Anticarcinogenic Agents
Antimetabolites
Anti-Inflammatory Agents
Anti-Infective Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Pathologic Processes
Sensory System Agents
Therapeutic Uses
Syndrome
Anti-Inflammatory Agents, Non-Steroidal
Analgesics
Neoplasms by Histologic Type
Disease
Enzyme Inhibitors
Protective Agents
Antiviral Agents
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Analgesics, Non-Narcotic
Peripheral Nervous System Agents
Antirheumatic Agents
Central Nervous System Agents
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on January 16, 2009