Clinical Trials /

Fludarabine Phosphate, Clofarabine, and Busulfan With Vorinostat in Treating Patients With Acute Leukemia in Remission or Relapse Undergoing Donor Stem Cell Transplant

NCT02083250

Description:

This phase I trial studies the side effects and best dose of vorinostat when given together with fludarabine phosphate, clofarabine, and busulfan in treating patients with acute leukemia that is under control (remission) or has returned (relapse) undergoing donor stem cell transplant. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, clofarabine, and busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with fludarabine phosphate, clofarabine, and busulfan before a donor stem cell transplant may be a better treatment for patients with acute leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Fludarabine Phosphate, Clofarabine, and Busulfan With Vorinostat in Treating Patients With Acute Leukemia in Remission or Relapse Undergoing Donor Stem Cell Transplant
  • Official Title: Fludarabine/Clofarabine/Busulfan Combined With SAHA in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 2012-0999
  • SECONDARY ID: NCI-2014-01982
  • SECONDARY ID: 2012-0999
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02083250

Conditions

  • Acute Lymphoblastic Leukemia in Remission
  • Acute Myeloid Leukemia in Remission
  • Allogeneic Hematopoietic Stem Cell Transplantation Recipient
  • Myelodysplastic Syndrome
  • Previously Treated Myelodysplastic Syndrome
  • Recurrent Acute Lymphoblastic Leukemia
  • Recurrent Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Anti-Thymocyte GlobulinAntithymocyte Globulin, Antithymocyte Serum, ATG, ATGAM, ATS, ThymoglobulinTreatment (vorinostat, chemotherapy, SCT)
Busulfan1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508Treatment (vorinostat, chemotherapy, SCT)
ClofarabineClofarex, ClolarTreatment (vorinostat, chemotherapy, SCT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (vorinostat, chemotherapy, SCT)
VorinostatL-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, ZolinzaTreatment (vorinostat, chemotherapy, SCT)

Purpose

This phase I trial studies the side effects and best dose of vorinostat when given together with fludarabine phosphate, clofarabine, and busulfan in treating patients with acute leukemia that is under control (remission) or has returned (relapse) undergoing donor stem cell transplant. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, clofarabine, and busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with fludarabine phosphate, clofarabine, and busulfan before a donor stem cell transplant may be a better treatment for patients with acute leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of SAHA (vorinostat) in combination with the
      preparative regimen fludarabine (fludarabine phosphate), clofarabine, and busulfan followed
      by allogeneic hematopoietic stem cell transplantation (SCT) for patients with advanced acute
      leukemia.

      SECONDARY OBJECTIVES:

      I. To determine the rate of graft versus host disease (GVHD), engraftment, progression-free
      survival (PFS) and overall survival (OS) for this treatment regimen.

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

      CONDITIONING REGIMEN: Patients receive vorinostat orally (PO) once daily (QD), fludarabine
      phosphate intravenously (IV) over 1 hour, clofarabine IV over 1 hour, and busulfan IV over 3
      hours on days -6 to -3. Patients receiving a transplant from a human leukocyte antigen
      (HLA)-matched unrelated donor, receive anti-thymocyte globulin IV over 4 hours on days -3 to
      -1.

      TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplant
      on day 0.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (vorinostat, chemotherapy, SCT)ExperimentalCONDITIONING REGIMEN: Patients receive vorinostat PO QD, fludarabine phosphate IV over 1 hour, clofarabine IV over 1 hour, and busulfan IV over 3 hours on days -6 to -3. Patients receiving a transplant from a HLA-matched unrelated donor, receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0.
  • Busulfan
  • Clofarabine
  • Fludarabine Phosphate
  • Vorinostat

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with biopsy-proven acute lymphoblastic leukemia, acute myeloid leukemia, or
             myelodysplastic syndrome in remission or relapse

          -  Estimated creatinine clearance at least 50 ml/min

          -  Bilirubin equal or less than 1.5 (unless Gilbert's syndrome)

          -  Serum glutamate pyruvate transaminase (SGPT) < 3 x upper limit of normal

          -  Alkaline phosphatase < 2 x upper limit of normal

          -  Pulmonary function with forced expiratory volume in 1 second (FEV1), forced vital
             capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) at least
             45% of expected corrected for hemoglobin; children unable to perform pulmonary
             functions must have an oxygen saturation greater than 92% at room air

          -  Left ventricular ejection fraction at least 45% on appropriate medical therapy; no
             uncontrolled arrhythmias or symptomatic cardiac disease

          -  Zubrod performance status 0-1 or Lansky/Karnofsky performance status (PS) equal or
             greater to 80%

          -  Patients must have a related, genotypically HLA identical donor, or they must have an
             unrelated donor who is 8/8 HLA match by high resolution typing

          -  Patient or patient's legal representative, parent(s) or guardian should provide
             written informed consent; assent of a minor if participant's age is at least seven and
             less than eighteen years

          -  Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing
             potential defined as not post-menopausal for 12 months and no previous surgical
             sterilization

        Exclusion Criteria:

          -  Patients with active central nervous system (CNS) disease

          -  Evidence of acute or chronic active hepatitis or cirrhosis

          -  Uncontrolled infection, including human immunodeficiency virus (HIV), human
             T-lymphotropic virus (HTLV)-1, hepatitis B or hepatitis C viremia

          -  Prior allogeneic SCT

          -  Prior autologous SCT in last 12 months

          -  Patients with acute myeloid leukemia (AML) in first remission after one course of
             induction and with favorable cytogenetics (t[8;21], inv 16, or t[15;17]) and/or
             molecular profile (nucleophosmin [NPM]1)

          -  Prior radiation to liver in form of total body or involved field
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of vorinostat when given in combination with fludarabine phosphate, clofarabine, and busulfan before stem cell transplant assessed using Common Terminology Criteria for Adverse Events version 4
Time Frame:30 days
Safety Issue:
Description:The 2-stage time-to-event continual reassessment method will be used. Toxicity will be tabulated by dose, type, and grade. The probability of toxicity over 30 days as a function of dose will be estimated by fitting a Bayesian binary outcome regression model.

Secondary Outcome Measures

Measure:Recurrence-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated by the Kaplan and Meier method.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated by the Kaplan and Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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