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

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ClinicalTrials.gov Identifier: NCT01252667
Recruitment Status : Active, not recruiting
First Posted : December 3, 2010
Last Update Posted : April 2, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

November 29, 2010
December 3, 2010
April 2, 2018
January 25, 2011
January 25, 2019   (Final data collection date for primary outcome 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 ]
    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).
  • Optimal dose of clofarabine in combination with 2, 3, or 4 Gy total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) from HLA-identical related and HLA-matched unrelated donors in patients with acute myeloid leukemia [ Time Frame: Day 14 after HCT (21 days after initiation of clofarabine) ]
    Optimal dose of clofarabine in combination with TBI in preparation for HCT from HLA-identical related and HLA-matched unrelated donors in patients with acute myeloid leukemia, will be assessed.
  • Optimal dose of clofarabine in combination with 2 Gy TBI in preparation for HCT from HLA-identical related and HLA-matched unrelated donors in patients with AML [ Time Frame: Periodically during study treatment ]
  • Efficacy of the optimal dose of clofarabine combined with 2 Gy TBI in reducing the relapse rate in patients with AML compared to our historical experience with fludarabine and 2 Gy TBI [ Time Frame: At 6 months ]
Complete list of historical versions of study NCT01252667 on ClinicalTrials.gov Archive Site
  • Engraftment rate [ Time Frame: At day 100 ]
    Engraftment rate will be determined.
  • Leukemia-free survival [ Time Frame: Up to 5 years ]
    Leukemia-free survival will be evaluated.
  • Minimal residual/recurring disease [ Time Frame: Up to 5 years ]
    Intensified monitoring by more frequent leukemia assessments and by adding molecular methods to improve leukemia-free and overall survival.
  • Non-relapse mortality (NRM) rate [ Time Frame: At day 100 ]
    NRM will be assessed.
  • Overall survival [ Time Frame: Up to 5 years ]
    Overall survival will be evaluated.
  • 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 ]
    PK of clofarabine will be assessed.
  • Prognostic cytogenetic markers [ Time Frame: Up to 5 years ]
    Potential prognostic markers will be assessed by polymerase chain reaction (PCR) to determine their prognostic value.
  • Prognostic genetic markers [ Time Frame: Up to 5 years ]
    Potential prognostic markers will be assessed by polymerase chain reaction to determine their prognostic value.
  • Leukemia-free survival [ Time Frame: At 1, 3 and 5 years. ]
  • NRM of less than 5% [ Time Frame: At day 100 ]
  • Engraftment rate of greater than or equal to 95% [ Time Frame: At day 100 ]
  • Monitoring genetic markers (FLT3, RAS, NPM1 and C/EBP gene mutations) by PCR (polymerase chain reaction) to determine their prognostic value. [ Time Frame: At days 28, 56, 84, 120, 180, then yearly for 5 years. ]
  • Intensified monitoring for minimal residual/recurring disease (by more frequent leukemia assessments and by adding molecular methods) to improve leukemia-free and overall survivals. [ Time Frame: At days 28, 56, 84, 120, 180 then yearly for 5 years. ]
  • Overall survival [ Time Frame: At 1, 3 and 5 years. ]
Not Provided
Not Provided
 
Clofarabine and Low-Dose Total-Body Irradiation in Treating Patients With Acute Myeloid Leukemia Undergoing Donor Peripheral Blood Stem Cell Transplant
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
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.

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.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Acute Myeloid Leukemia
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo allogeneic hematopoietic PBSCT
    Other Names:
    • Allogeneic Hematopoietic Cell Transplantation
    • allogeneic stem cell transplantation
    • HSC
    • HSCT
  • Drug: Clofarabine
    Given IV
    Other Names:
    • Clofarex
    • Clolar
  • Drug: Cyclosporine
    Given PO
    Other Names:
    • 27-400
    • Ciclosporin
    • CsA
    • Cyclosporin
    • Cyclosporin A
    • Gengraf
    • Neoral
    • OL 27-400
    • Sandimmun
    • Sandimmune
    • SangCya
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mycophenolate Mofetil
    Given PO
    Other Names:
    • Cellcept
    • MMF
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Undergo allogeneic hematopoietic PBSCT
    Other Names:
    • PBPC transplantation
    • PBSCT
    • Peripheral Blood Progenitor Cell Transplantation
    • peripheral stem cell support
    • Peripheral Stem Cell Transplant
    • peripheral stem cell transplantation
  • Other: Pharmacological Study
    Optional correlative studies
  • Radiation: Total-Body Irradiation
    Undergo TBI
    Other Names:
    • TOTAL BODY IRRADIATION
    • Whole-Body Irradiation
Experimental: Treatment (chemotherapy and low-dose TBI before PBSCT)

CONDITIONING 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.

Interventions:
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
  • Drug: Clofarabine
  • Drug: Cyclosporine
  • Other: Laboratory Biomarker Analysis
  • Drug: Mycophenolate Mofetil
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Other: Pharmacological Study
  • Radiation: Total-Body Irradiation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
44
78
Not Provided
January 25, 2019   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
2 Years and older   (Child, Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01252667
2430.00
NCI-2010-02247 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2430.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P01CA078902 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Principal Investigator: Brenda Sandmaier Fred Hutch/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP