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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00796068
First received: November 21, 2008
Last updated: August 13, 2015
Last verified: August 2015
  Purpose

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.


Condition Intervention Phase
Acute Biphenotypic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Adult Myelodysplastic Syndrome
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Acute Myeloid Leukemia in Remission
Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Childhood Myelodysplastic Syndrome
Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Refractory Anemia With Excess Blasts
Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Drug: Cyclosporine
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Drug: Mycophenolate Mofetil
Radiation: Total-Body Irradiation
Drug: Treosulfan
Procedure: Umbilical Cord Blood Transplantation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Treosulfan Based Preparative Regimen

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Incidence of graft failure/rejection [ Time Frame: By day 42 ] [ Designated as safety issue: No ]
    For both arms a graft failure rate of 5% will be accepted. Arm 1 will be terminated if graft failure rates exceed 10% after maximum dose escalation. Arm 2 will be terminated if graft failure rates exceed 15% after maximum dose escalation.

  • Incidence of non-relapse mortality [ Time Frame: At day 200 ] [ Designated as safety issue: Yes ]
    If rates exceed 25% in either arm of the study, that arm will be terminated.


Secondary Outcome Measures:
  • Incidence of acute GVHD [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Determined based on the organ stage, response to treatment and whether GVHD was a major cause of death.

  • Incidence of acute or chronic GVHD [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
    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 clinically significant infections [ Time Frame: At 6 months ] [ Designated as safety issue: Yes ]
    Collected and graded according to the modified National Cancer Institute (NCI) Common Toxicity Criteria.

  • Incidence of platelet engraftment [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
  • Incidence of relapse [ Time Frame: Assessed up to 2 years ] [ Designated as safety issue: No ]
  • Non-relapse mortality [ Time Frame: Assessed up to 2 years ] [ Designated as safety issue: Yes ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.

  • One year survival [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.

  • Overall survival [ Time Frame: Assessed up to 2 years ] [ Designated as safety issue: No ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.

  • Progression-free survival [ Time Frame: Assessed up to 2 years ] [ Designated as safety issue: No ]
    Summarized using Kaplan-Meier and cumulative incidence estimates.


Estimated Enrollment: 80
Study Start Date: October 2008
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 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.

Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • CYCLOSPORINE
  • 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
  • FLUDARABINE PHOSPHATE
  • Oforta
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
  • MYCOPHENOLATE MOFETIL
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
  • 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
  • TREOSULFAN
  • Treosulphan
  • Tresulfon
Procedure: Umbilical Cord Blood Transplantation
Undergo single or double unit UCBT
Other Names:
  • Cord Blood Transplantation
  • UCB transplantation
  • 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.
Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • CYCLOSPORINE
  • 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
  • FLUDARABINE PHOSPHATE
  • Oforta
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF
  • MYCOPHENOLATE MOFETIL
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
  • 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
  • TREOSULFAN
  • Treosulphan
  • Tresulfon
Procedure: Umbilical Cord Blood Transplantation
Undergo single or double unit UCBT
Other Names:
  • Cord Blood Transplantation
  • UCB transplantation
  • umbilical cord blood transplantation

Detailed Description:

PRIMARY OBJECTIVES:

I. Combined incidence of primary graft failure/rejection and secondary graft failure in Arm 1 and Arm 2.

II. Day 200 non-relapse mortality in Arm 1 and Arm 2.

SECONDARY OBJECTIVES:

I. Incidence of platelet engraftment by six months.

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

III. Incidence of one year chronic GVHD.

IV. Incidence of clinically significant infections at 6 months, 1 year, 2 years.

V. Probability of one and two year survival.

VI. Incidence of one and two year relapse or disease progression.

VII. Kinetics of immune reconstitution, with both functional and quantitative assays (Fred Hutchinson Cancer Research Center [FHCRC] only).

VIII. Examination of possible immunologic factors leading to emergence of a dominant unit (FHCRC only).

OUTLINE:

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 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 periodically.

  Eligibility

Ages Eligible for Study:   up to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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; Lansky (for children) score >= 50
  • Patients > 50 must have Karnofsky performance score >= 70 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
  • 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 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
  • Second hematopoietic cell transplant: must be >= 3 months after prior myeloablative transplant
  • DONOR: 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 107 TNC/kg

Exclusion Criteria:

  • Patients =< 65 years with an available 5-6/6 human leukocyte antigen (HLA)-A, B, DRB1 matched sibling donor
  • 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)
  • Acute myeloid leukemia (AML) in first complete response (CR1) with favorable prognostic cytogenetics (t8;21, t15;17, inv16) and low risk MDS (International Prognostic Scoring System [IPSS] score 0)
  • DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight
  • DONOR: Any cord blood units without full maternal testing and negative results for hepatitis A, B, C, HIV, and human T-lymphotropic virus (HTLV)-1 viruses; any additional available virology results on the unit itself will be reviewed but are not mandated, complete or always available
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00796068

Locations
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion Active, not recruiting
Aurora, Colorado, United States, 80045
United States, Oregon
Oregon Health and Science University Completed
Portland, Oregon, United States, 97239
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Colleen Delaney    206-667-1385    sdelaney@fredhutch.org   
Principal Investigator: Colleen Delaney         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Colleen Delaney Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00796068     History of Changes
Other Study ID Numbers: 2275.00, NCI-2010-00299, 2275, 2275.00, P30CA015704
Study First Received: November 21, 2008
Last Updated: August 13, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Leukemia
Leukemia, Biphenotypic, Acute
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myeloid, Chronic-Phase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Syndrome
Anemia
Bone Marrow Diseases
Disease
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Busulfan
Cyclosporine
Cyclosporins
Fludarabine

ClinicalTrials.gov processed this record on August 27, 2015