Clinical Trials /

Clofarabine and Low-Dose Total-Body Irradiation in Treating Patients With Acute Myeloid Leukemia Undergoing Donor Peripheral Blood Stem Cell Transplant

NCT01252667

Description:

This phase II trial studies the side effects and how well clofarabine works when given together with low-dose total-body irradiation (TBI) in treating patients with acute myeloid leukemia (AML) undergoing donor peripheral blood stem cell transplant (PBSCT). Giving chemotherapy and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Clofarabine and Low-Dose Total-Body Irradiation in Treating Patients With Acute Myeloid Leukemia Undergoing Donor Peripheral Blood Stem Cell Transplant
  • Official Title: A Phase II Study of Optimally Dosed Clofarabine in Combination With Low-Dose TBI to Decrease Relapse Rates After Related or Unrelated Donor Hematopoietic Cell Transplantation in Patients With AML

Clinical Trial IDs

  • ORG STUDY ID: 2430.00
  • SECONDARY ID: NCI-2010-02247
  • SECONDARY ID: 2430.00
  • SECONDARY ID: P01CA078902
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT01252667

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
ClofarabineClofarex, ClolarTreatment (chemotherapy and low-dose TBI before PBSCT)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (chemotherapy and low-dose TBI before PBSCT)
Mycophenolate MofetilCellcept, MMFTreatment (chemotherapy and low-dose TBI before PBSCT)

Purpose

This phase II trial studies the side effects and how well clofarabine works when given together with low-dose total-body irradiation (TBI) in treating patients with acute myeloid leukemia (AML) undergoing donor peripheral blood stem cell transplant (PBSCT). Giving chemotherapy and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose of clofarabine in combination with 2, 3, or 4 Gy
      TBI in preparation for hematopoietic cell transplantation (HCT) from human leukocyte antigen
      (HLA)-identical related and HLA-matched unrelated donors in patients with AML. (Part 1)

      II. To determine the efficacy of the maximum tolerated dose of clofarabine combined with 2,
      3, or 4 Gy TBI in reducing the 6 month relapse rate in patients with AML compared to our
      historical experience with fludarabine and 2 Gy TBI. A satisfactory improvement will be
      considered 6 month relapse rate declines from 35% to 20% among high-risk (objective for low
      risk group terminated August 2014). (Part 2)

      SECONDARY OBJECTIVES:

      I. Leukemia-free and overall survivals.

      II. Non-relapse mortality (NRM) of < 5% at 100 days.

      III. Engraftment rate of >= 95%.

      IV. Prognostic significance of cytogenetics and genetic markers not detected by traditional
      karyotype analysis, with special respect to tyrosine kinase receptor mutations (such as
      fms-like tyrosine kinase 3 [FLT3]), retrovirus-associated deoxyribonucleic acid (DNA)
      sequences (RAS)- and nucleophosmin gene mutations along with CCAAT/enhancer binding protein,
      alpha (C/EBP) mutations.

      V. Rigorous monitoring for minimal residual/recurring disease by standard morphologic, flow
      cytometric, and molecular techniques in order to facilitate early intervention.

      VI. To evaluate the pharmacokinetics of clofarabine (pharmacokinetic samples discontinued
      January 2017).

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

      CONDITIONING REGIMEN: Patients receive clofarabine intravenously (IV) over 2 hours on days -6
      to -2. Patients also undergo TBI on day 0.

      IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine orally (PO) every 12
      hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on
      days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days
      -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40
      with taper to day 96.

      TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

      After completion of study treatment, patients are followed up at 4 months and then every year
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy and low-dose TBI before PBSCT)ExperimentalCONDITIONING REGIMEN: Patients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.
  • Clofarabine
  • Cyclosporine
  • Mycophenolate Mofetil

Eligibility Criteria

        Inclusion Criteria:

          -  Patients age >= 55 years with AML OR patients age < 55 years with AML, who also
             through pre-existing medical conditions or prior therapy are considered to be at high
             risk for serious toxicities associated with a conventional, high-dose preparative
             regimen

          -  Patients must be in morphologic leukemia-free state (marrow blasts < 5%) without
             evidence of extramedullary disease within 21 days of HCT

          -  Only patients with Relapse Risk Score > 0 ("high risk") will be enrolled during Part
             1; patients with all Relapse Risk Scores will be enrolled during Part 2 (low risk
             group terminated August 2014)

          -  HLA-identical related or HLA-matched unrelated donor available

          -  A signed informed consent form or minor assent form

          -  DONOR: FHCRC matching allowed will be grade 1.0 to 2.1: unrelated donors who are
             prospectively: matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only
             a single allele disparity will be allowed for HLA-A, B, or C as defined by high
             resolution typing

          -  DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion;
             donors are excluded when preexisting immunoreactivity is identified that would
             jeopardize donor hematopoietic cell engraftment; this determination is based on the
             standard practice of the individual institution; the recommended procedure for
             patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
             reactive antibody (PRA) screens to class I and class II antigens for all patients
             before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
             cytotoxic cross matches should be obtained; the donor should be excluded if any of the
             cytotoxic cross match assays are positive; for those patients with an HLA Class I
             allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be
             obtained regardless of the PRA results

          -  DONOR: Patient and donor pairs homozygous at a mismatched allele are considered a
             two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this
             type of mismatch is not allowed

          -  DONOR: Peripheral blood stem cells (PBSC) only will be permitted as a HSC source on
             this protocol

        Exclusion Criteria:

          -  AML French-American-British (FAB) M3 in first complete remission (CR1)

          -  Active AML involvement of the central nervous system (CNS) with disease refractory to
             intrathecal chemotherapy

          -  Presence of circulating leukemic blasts in the peripheral blood detected by standard
             morphology

          -  Patients who are human immunodeficiency virus (HIV)+ (HIV+ patients registered at Fred
             Hutchinson Cancer Research Center [FHCRC] should be offered treatment on Protocol
             1410)

          -  Fertile men and women unwilling to use contraceptive techniques during and for 12
             months following treatment

          -  Left ventricular ejection fraction < 35% (or, if unable to obtain ejection fraction,
             shortening fraction of < 26%); ejection fraction is required if age > 50 years or
             there is a history of anthracycline exposure or history of cardiac disease; patients
             with a shortening fraction < 26% may be enrolled if approved by a cardiologist

          -  Diffusion capacity of the lung for carbon monoxide (DLCO) < 40% (corrected), total
             lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or
             receiving supplementary continuous oxygen

          -  The FHCRC principal investigator (PI) of the study must approve enrollment of all
             patients with pulmonary nodules

          -  Patients with clinical or laboratory evidence of liver disease will be evaluated for
             the cause of liver disease, its clinical severity in terms of liver function, and the
             degree of portal hypertension; patients will be excluded if they are found to have
             fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension,
             alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices,
             hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by
             prolongation of the prothrombin time, ascites related to portal hypertension, bridging
             fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral
             hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease

          -  Serum creatinine should be within normal limits as specified by institutional
             guidelines; for patients with serum creatinine > upper limit of normal, a 24-hour
             creatinine clearance will be performed and should be equal to or more than the lower
             limit of normal

          -  Karnofsky score < 60 or Lansky score < 50

          -  Patients with poorly controlled hypertension and on multiple antihypertensives

          -  Females who are pregnant or breastfeeding

          -  Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
             or those with non-hematologic malignancies (except non-melanoma skin cancers) who have
             been rendered with no evidence of disease, but have a greater than 20% chance of
             having disease recurrence within five years; this exclusion does not apply to patients
             with non-hematologic malignancies that do not require therapy

          -  The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine
             kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose
             cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the
             initiation of conditioning

          -  Fungal infections with radiological progression after receipt of amphotericin B or
             active triazole for greater than 1 month

          -  Patients with active bacterial or fungal infections unresponsive to medical therapy

          -  DONOR: Marrow donors

          -  DONOR: Donors who are HIV-positive and/or medical conditions that would result in
             increased risk to the donor filgrastim (G-CSF) mobilization and PBSC collections

          -  DONOR: Identical twin

          -  DONOR: Any contraindication to the administration of subcutaneous G-CSF at a dose of
             16 mg/kg/day for 5 consecutive days

          -  DONOR: Serious medical or psychological illness

          -  DONOR: Pregnant or lactating females

          -  DONOR: Prior malignancy within the preceding 5 years, with the exception of
             non-melanoma skin cancers

          -  DONOR: Children < 12 years old
      
Maximum Eligible Age:N/A
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy of the optimal dose of clofarabine combined with 2, 3, or 4 Gy total body irradiation (TBI) in reducing the relapse rate in patients with acute myeloid leukemia (AML) compared to our historical experience with fludarabine and 2, 3, or 4 Gy TBI
Time Frame:At 6 months
Safety Issue:
Description:Rate of disease relapse or progression, defined as the presence of > 5% blasts by morphology on a marrow aspirate or the presence of circulating blasts in the peripheral blood. A satisfactory improvement will be considered declines from 35% to 20% among high-risk and from 15% to 5% among low risk patients (low risk group terminated August 2014).

Secondary Outcome Measures

Measure:Engraftment rate
Time Frame:At day 100
Safety Issue:
Description:Engraftment rate will be determined.
Measure:Leukemia-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Leukemia-free survival will be evaluated.
Measure:Minimal residual/recurring disease
Time Frame:Up to 5 years
Safety Issue:
Description:Intensified monitoring by more frequent leukemia assessments and by adding molecular methods to improve leukemia-free and overall survival.
Measure:Non-relapse mortality (NRM) rate
Time Frame:At day 100
Safety Issue:
Description:NRM will be assessed.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Overall survival will be evaluated.
Measure:Pharmacokinetics (PK) of clofarabine
Time Frame:After the first clofarabine infusion at 2, 3, 4, 5, and 6 hours; prior to the 2nd, 3rd, 4th, and 5th doses of clofarabine; within 2 hours before the infusion of peripheral blood stem cells
Safety Issue:
Description:PK of clofarabine will be assessed.
Measure:Prognostic cytogenetic markers
Time Frame:Up to 5 years
Safety Issue:
Description:Potential prognostic markers will be assessed by polymerase chain reaction (PCR) to determine their prognostic value.
Measure:Prognostic genetic markers
Time Frame:Up to 5 years
Safety Issue:
Description:Potential prognostic markers will be assessed by polymerase chain reaction to determine their prognostic value.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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