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Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematological Cancer Who Are Undergoing Umbilical Cord Blood Transplant

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ClinicalTrials.gov Identifier: NCT00796068
Recruitment Status : Active, not recruiting
First Posted : November 24, 2008
Last Update Posted : October 14, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE November 21, 2008
First Posted Date  ICMJE November 24, 2008
Last Update Posted Date October 14, 2019
Actual Study Start Date  ICMJE October 29, 2008
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • Incidence of graft failure/rejection [ Time Frame: Up to 2 years ]
  • Incidence of secondary graft failure [ Time Frame: Up to 2 years ]
  • Incidence of non-relapse mortality [ Time Frame: At day -200 ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 21, 2008)
  • Combined incidence of primary graft failure/rejection and secondary graft failure
  • Non-relapse mortality at day 200
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • One year survival [ Time Frame: At 1 year ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.
  • Overall survival [ Time Frame: Up to 2 years ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.
  • Non-relapse mortality [ Time Frame: Up to 2 years ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.
  • Incidence of platelet engraftment [ Time Frame: At 6 months ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.
  • Incidence of acute graft-versus-host disease (GVHD) [ Time Frame: Day 100 ]
    Determined based on the organ stage, response to treatment and whether GVHD was a major cause of death.
  • Incidence of acute or chronic graft-versus-host disease (GVHD) [ Time Frame: At 1 year ]
    Overall GVHD is determined based on the organ stage, response to treatment and whether GVHD was a major cause of death. Chronic GVHD will be defined according to the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Described as mild, moderate, or severe as graded according to the attached Organ Scoring Sheet. Symptoms consistent with both chronic and acute GVHD occurring after day 100 will be considered overlap chronic GVHD syndrome.
  • Incidence of relapse or disease progression [ Time Frame: Up to 2 years ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.
  • Progression-free survival [ Time Frame: Up to 2 years ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.
  • Incidence of clinically significant infections [ Time Frame: At 6 months ]
    Collected and graded according to the modified National Cancer Institute Common Toxicity Criteria.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2008)
  • 1-year survival
  • Overall survival
  • Incidence of platelet engraftment at 6 months
  • Incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) at day 100 and 1 year
  • Incidence of chronic GVHD at 1 year
  • Incidence of clinically significant infections at 6 months, 1 year, and 2 years
  • Progression-free survival
  • Relapse
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematological Cancer Who Are Undergoing Umbilical Cord Blood Transplant
Official Title  ICMJE Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Treosulfan Based Preparative Regimen
Brief Summary This phase II trial studies how well giving treosulfan together with fludarabine phosphate and total-body irradiation (TBI) works in treating patients with hematological cancer who are undergoing umbilical cord blood transplant (UCBT). Giving chemotherapy, such as treosulfan and fludarabine phosphate, and TBI before a donor UCBT helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from a related or unrelated donor, that do not exactly match the patient's blood, are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
Detailed Description

PRIMARY OBJECTIVES:

I. Graft failure/rejection and secondary graft failure.

II. Day -200 non-relapse mortality.

SECONDARY OBJECTIVES:

I. Platelet engraftment by six months.

II. Grade II-IV and III-IV acute graft-versus-host disease (GVHD) at day 100 and one year.

III. Chronic GVHD.

IV. Clinically significant infections.

V. Overall survival.

VI. Relapse or disease progression.

VII. Immune reconstitution (Fred Hutchinson Cancer Research Center [FHCRC] only).

VIII. Emergence of a dominant unit (FHCRC only).

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (low risk for graft failure): Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) over 1 hour once daily (QD) on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or orally (PO) 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD.

ARM II (high risk for graft failure): Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I.

After completion of the study treatment, patients are followed up at 6 months and 1 and 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Biphenotypic Leukemia
  • Acute Lymphoblastic Leukemia in Remission
  • Acute Myeloid Leukemia in Remission
  • Blasts Under 5 Percent of Bone Marrow Nucleated Cells
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Myelodysplastic Syndrome
Intervention  ICMJE
  • Drug: Cyclosporine
    Given IV or PO
    Other Names:
    • 27-400
    • Ciclosporin
    • CsA
    • Cyclosporin
    • Cyclosporin A
    • Gengraf
    • Neoral
    • OL 27-400
    • Sandimmun
    • Sandimmune
    • SangCya
  • Drug: Fludarabine Phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
    • Beneflur
    • Fludara
    • SH T 586
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mycophenolate Mofetil
    Given IV
    Other Names:
    • Cellcept
    • MMF
  • Radiation: Total-Body Irradiation
    TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section)
    Other Names:
    • Total Body Irradiation
    • Whole-Body Irradiation
  • Drug: Treosulfan
    Given IV
    Other Names:
    • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
    • Dihydroxybusulfan
    • Ovastat
    • Treosulphan
    • Tresulfon
  • Procedure: Umbilical Cord Blood Transplantation
    Undergo single or double unit UCBT
    Other Names:
    • Cord Blood Transplantation
    • UCB transplantation
Study Arms  ICMJE
  • Experimental: Arm I (low risk for graft failure)

    Patients receive a conditioning regimen comprising fludarabine phosphate IV over 1 hour QD on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0.

    Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or PO 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD.

    Interventions:
    • Drug: Cyclosporine
    • Drug: Fludarabine Phosphate
    • Other: Laboratory Biomarker Analysis
    • Drug: Mycophenolate Mofetil
    • Radiation: Total-Body Irradiation
    • Drug: Treosulfan
    • Procedure: Umbilical Cord Blood Transplantation
  • Experimental: Arm II (high risk for graft failure)
    Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I.
    Interventions:
    • Drug: Cyclosporine
    • Drug: Fludarabine Phosphate
    • Other: Laboratory Biomarker Analysis
    • Drug: Mycophenolate Mofetil
    • Radiation: Total-Body Irradiation
    • Drug: Treosulfan
    • Procedure: Umbilical Cord Blood Transplantation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 16, 2015)
130
Original Estimated Enrollment  ICMJE
 (submitted: November 21, 2008)
28
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an evaluable marrow sample (> 25% of normal cellularity for age collected less than one month prior to start of conditioning; patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible; reasonable attempts must be made to obtain an adequate specimen for morphologic assessment, including possible repeat procedures; these patients must be discussed with the principal investigator prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with principal investigator (PI) approval
  • Myelodysplastic syndrome (MDS): Any 2001 World Health Organization (WHO) classification subtype; refractory anemia with excess blasts (RAEB)-2 patients may proceed directly to transplant, but may also be considered for induction chemotherapy before transplant; patients with >= 20% morphologic marrow blasts require induction therapy to reduce morphologic marrow blasts below 5% before transplant
  • Chronic myelogenous leukemia: All types, except refractory blast crisis; chronic phase patients must have failed or been intolerant to Gleevec or other tyrosine kinase inhibitors
  • Patients =< 50 must have performance status score: Karnofsky (for adults) >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-1; Lansky (for children) score >= 50
  • Patients > 50 must have Karnofsky performance score >= 70 or ECOG 0-1 and comorbidity index < 5
  • Adequate cardiac function defined as absence of decompensated congestive heart failure or uncontrolled arrhythmia AND left ventricular ejection fraction >= 35% OR fractional shortening > 22%
  • Adequate pulmonary function defined as absence of oxygen (O2) requirements and one of the following:

    • Diffusion lung capacity for carbon monoxide (DLCO) corrected >= 70% mm Hg
    • DLCO corrected between 60% - 69% mm Hg and partial pressure of oxygen (pO2) >= 70 mm Hg
    • DLCO corrected between 50% - 59% mm Hg and pO2 >= 80 mm Hg
    • Pediatric patients unable to perform pulmonary function tests must have O2 saturation > 92% on room air; may not be on supplemental oxygen
  • Adequate hepatic function; 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, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded
  • Adequate renal function defined as creatinine =< 2.0 mg/dl (adults) or estimated creatinine clearance > 40 ml/min (pediatrics); all adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min
  • If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease to proceed
  • Prior hematopoietic cell transplant: must be >= 3 months after previous transplant
  • DONOR: Human leukocyte antigen (HLA) matching:

    • Minimum requirement: The cord blood (CB) graft(s) must be matched at a minimum at 4/6 HLA-A, B, DRB1 loci with the recipient; therefore 0-2 mismatches at the A or B or DRB1 loci based on intermediate resolution A, B antigen and DRB1 allele typing for determination of HLA-match is allowed
    • HLA-matching determined by high resolution typing is allowed per institutional guidelines as long as the minimum criteria (above) are met
  • DONOR: Selection of two CB units is mandatory when a single cord blood unit does not meet the following criteria in the table below

    • Match grade

      • 6/6

        • Single unit allowed for total nucleated cell (TNC) dose >= 2.5 x 10^7/kg
      • 5/6, 4/6

        • Single unit allowed for TNC dose >= 4.0 (+/- 0.5) x 10^7/kg
    • If two CB units are used, the total cell dose of the combined units must be at least 3.0 x 10^7 TNC per kilogram recipient weight based on pre-cryopreservation numbers, with each CB unit containing a MINIMUM of 1.5 x 10^7 TNC/kg
  • DONOR: The minimum recommended CD34/kg cell dose should be 2 x 10^5 CD34/kg, total dose from a single or combined double
  • DONOR: The unmanipulated CB unit(s) will be Food and Drug Administration (FDA) licensed or will be obtained under a separate investigational new drug (IND), such as the National Marrow Donor Program (NMDP) Protocol 10-CBA conducted under BB IND-7555 or another IND sponsored by (1) a participating institution or (2) an investigator at FHCRC or one of the participating institutions
  • DONOR (FHCRC only): Up to 5% of the unmanipulated cord blood product (s), when ready for infusion, may be withheld for research purposes as long as thresholds for infused TNC dose are met; these products will be used to conduct studies involving the kinetics of engraftment and immunobiology of double cord transplantation

Exclusion Criteria:

  • Pregnancy or breastfeeding
  • Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
  • Uncontrolled viral or bacterial infection at the time of study enrollment
  • Active or recent (prior 6 month) invasive fungal infection without infectious diseases (ID) consult and approval
  • Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiation of conditioning (day -6)
  • DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight
  • DONOR: Any cord blood units that have not passed donor screening for infectious disease markers as recommended by NMDP will not be used unless a waiver is signed by the clinical attending allowing use of CB unit. Cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00796068
Other Study ID Numbers  ICMJE 2275.00
NCI-2010-00299 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2275
2275.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG2808000 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Filippo Milano Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date October 2019

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