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Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

This study is currently recruiting participants.
Verified September 2017 by Fred Hutchinson Cancer Research Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT01690520
First Posted: September 21, 2012
Last Update Posted: September 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
September 19, 2012
September 21, 2012
September 18, 2017
December 11, 2012
April 30, 2018   (Final data collection date for primary outcome measure)
Time to engraftment defined as the first 2 consecutive days in which absolute neutrophil count >= 500 in both arms (standard myeloablative cord blood transplantation with and without off-the-shelf expanded cord blood progenitors) [ Time Frame: Up to 2 years ]
The log-rank test will be used. Groups will be compared using Gray's test.
Time to engraftment (ANC greater than or equal to 500) in both arms (standard myeloablative CBT with and without off-the-shelf expanded cord blood progenitors) [ Time Frame: Up to 2 years ]
The log-rank test will be used.
Complete list of historical versions of study NCT01690520 on ClinicalTrials.gov Archive Site
  • Incidence and severity of acute and chronic graft versus host disease [ Time Frame: Up to 2 years ]
    Will be measured.
  • Incidence of infectious complications [ Time Frame: Up to 100 days post-transplant ]
    Will be measured.
  • Non-relapse mortality [ Time Frame: Up to 100 days post-transplant ]
    Will be measured.
  • Overall survival [ Time Frame: Up to 2 years ]
    Will be measured.
  • Platelet engraftment (20k) [ Time Frame: Up to 2 years ]
    Groups will be compared using Gray's test.
  • Time to engraftment, defined as the first of 2 consecutive days in which ANC is at least 500 [ Time Frame: Up to 2 years ]
  • Relative contribution to engraftment of the expanded cord blood product and the unmanipulated cord blood unit(s) in early and long-term engraftment, determined by frequent determination of donor chimerism in the peripheral blood [ Time Frame: Up to 2 years ]
  • Time to ANC greater than or equal to 100 [ Time Frame: Up to 2 years ]
  • Time to ANC greater than or equal to 500 [ Time Frame: Up to 2 years ]
  • Time to platelet engraftment (20k) [ Time Frame: Up to 2 years ]
  • Time to platelet engraftment (50k) [ Time Frame: Up to 2 years ]
  • Duration of initial hospitalization [ Time Frame: Up to 2 years ]
  • Incidence of infectious complications [ Time Frame: Up to 100 days post-transplant ]
  • Non-relapse mortality (NRM) [ Time Frame: Day 200 ]
  • NRM [ Time Frame: 1 year ]
  • Incidence and severity of acute and chronic GVHD [ Time Frame: Up to 2 years ]
  • Infusional toxicity greater than or equal to grade 3 [ Time Frame: Up to 2 years ]
  • Graft failure (primary and secondary) [ Time Frame: Up to 2 years ]
  • Kinetics of immune system recovery as measured by T and B cell subsets, T cell receptor excision circles (TREC), spectratyping and T cell receptor (TCR) sequencing [ Time Frame: Up to 2 years ]
  • Duration of initial hospitalization [ Time Frame: Up to 2 years ]
    Will be measured.
  • Graft failure (primary and secondary) [ Time Frame: Up to 2 years ]
    Will be measured.
  • In vivo persistence of the ex vivo expanded cord blood product [ Time Frame: Up to 2 years ]
    Will be measured.
  • Infusional toxicity greater than or equal to grade 3 [ Time Frame: Day 0 (day of transplant) ]
    Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
  • Kinetics of immune system recovery as measured by T and B cell subsets, T cell receptor excision circles, and T cell receptor sequencing [ Time Frame: Up to 2 years ]
    The kinetics and durability of hematopoietic reconstitution will be assessed and the relative contribution to engraftment of the expanded cord blood product and the unmanipulated unit(s) will be determined by frequent peripheral blood donor chimerism assays.
Not Provided
 
Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes
Multi-center, Open-Label Randomized Study of Single or Double Myeloablative Cord Blood Transplantation With or Without Infusion of Off-The-Shelf Ex Vivo Expanded Cryopreserved Cord Blood Progenitor Cells in Patients With Hematologic Malignancies
This randomized phase II trial studies how well donor umbilical cord blood transplant with or without ex-vivo expanded cord blood progenitor cells works in treating patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndromes. Giving chemotherapy and total-body irradiation before a donor umbilical cord blood transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy stem cells and ex-vivo expanded cord blood progenitor cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether giving donor umbilical cord blood transplant plus ex-vivo expanded cord blood progenitor cells is more effective than giving a donor umbilical cord blood transplant alone.

PRIMARY OBJECTIVES:

I. Compare the time to neutrophil engraftment (absolute neutrophil count [ANC] >= 500) in patients receiving a standard of care myeloablative cord blood transplant (CBT) augmented with an off-the-shelf pre-expanded and cryopreserved cord blood product to those who do not receive the product.

SECONDARY OBJECTIVES:

I. Provide initial data on clinical and economic benefit, such as time to platelet engraftment, duration of initial hospitalization, transplant-related mortality (TRM), death without engraftment, and incidence of severe infections in the first 100 days post-transplant.

II. The kinetics of immune system recovery will also be evaluated in both arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Standard of Care Arm:

CONDITIONING REGIMEN: One of two possible conditioning regimens is chosen by the attending physician: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6., and undergo high dose total-body irradiation (TBI) twice daily (BID) on days -4 to -1 OR Patients receive fludarabine phosphate IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo middle intensity TBI once daily (QD) on days -2 to -1.

TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated umbilical cord blood (UCB) transplant on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive cyclosporine IV over 1 hour BID (adults) or thrice daily (TID) (children) or orally (PO) on days -3 to 100 with taper beginning on day 101. Patients also receive mycophenolate mofetil (MMF) IV TID on days 0-7 then may receive MMF PO TID. Patients remain on MMF TID for a minimum of 30 days, and then may begin taper if there is no evidence of GVHD and are well-engrafted from one donor unit.

Experimental Arm:

CONDITIONING REGIMEN: Patients receive the conditioning regimen chosen by the attending physician as in Standard of Care Arm.

TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated UCB transplant on day 0. Patients also receive an infusion of ex vivo-expanded cord blood progenitors at least 4 hours after completion of UCB transplant.

GVHD PROPHYLAXIS: Patients receive cyclosporine IV or PO and mycophenolate mofetil IV or PO as in Standard of Care Arm.

After completion of study treatment, patients are followed up periodically for 2 years.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Acute Biphenotypic Leukemia
  • Acute Erythroid Leukemia
  • Acute Lymphoblastic Leukemia in Remission
  • Acute Megakaryoblastic Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia in Remission
  • Blasts Under 10 Percent of Bone Marrow Nucleated Cells
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndrome
  • Myelodysplastic Syndrome With Excess Blasts
  • Pancytopenia
  • Refractory Anemia
  • Secondary Acute Myeloid Leukemia
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Cyclosporine
    Given IV or PO
    Other Names:
    • 27-400
    • Ciclosporin
    • CsA
    • Cyclosporin
    • Cyclosporin A
    • Gengraf
    • Neoral
    • OL 27-400
    • Sandimmun
    • Sandimmune
    • SangCya
  • Procedure: Double-Unit Umbilical Cord Blood Transplantation
    Undergo double-unit unmanipulated umbilical cord blood transplant
  • Procedure: Ex Vivo-Expanded Cord Blood Progenitor Cell Infusion
    Given IV
  • 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 or PO
    Other Names:
    • Cellcept
    • MMF
  • Drug: Thiotepa
    Given IV
    Other Names:
    • 1,1',1''-Phosphinothioylidynetrisaziridine
    • Girostan
    • N,N', N''-Triethylenethiophosphoramide
    • Oncotiotepa
    • STEPA
    • Tepadina
    • TESPA
    • Tespamin
    • Tespamine
    • Thio-Tepa
    • Thiofosfamide
    • Thiofozil
    • Thiophosphamide
    • Thiophosphoramide
    • Thiotef
    • Tifosyl
    • TIO TEF
    • Tio-tef
    • Triethylene thiophosphoramide
    • triethylenethiophosphoramide
    • Tris(1-aziridinyl)phosphine sulfide
    • TSPA
    • WR 45312
  • Radiation: Total-Body Irradiation
    Undergo high dose or middle intensity TBI
    Other Names:
    • TOTAL BODY IRRADIATION
    • Whole-Body Irradiation
  • Procedure: Umbilical Cord Blood Transplantation
    Undergo single-unit unmanipulated umbilical cord blood transplant
    Other Names:
    • Cord Blood Transplantation
    • UCB transplantation
  • Active Comparator: Arm I (standard of care)

    CONDITIONING REGIMEN: One of two possible conditioning regimens is chosen by the attending physician: Patients receive fludarabine phosphate IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6., and undergo high dose TBI BID on days -4 to -1 OR Patients receive fludarabine phosphate IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo middle intensity TBI QD on days -2 to -1.

    TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated UCB transplant on day 0.

    GVHD PROPHYLAXIS: Patients receive cyclosporine IV over 1 hour BID (adults) or TID (children) or PO on days -3 to 100 with taper beginning on day 101. Patients also receive MMF IV TID a day on days 0-7 then may receive MMF PO TID. Patients remain on MMF TID for a minimum of 30 days, and then may begin a taper if there is no evidence of GVHD and are well-engrafted from one donor unit.

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cyclosporine
    • Procedure: Double-Unit Umbilical Cord Blood Transplantation
    • Drug: Fludarabine Phosphate
    • Other: Laboratory Biomarker Analysis
    • Drug: Mycophenolate Mofetil
    • Drug: Thiotepa
    • Radiation: Total-Body Irradiation
    • Procedure: Umbilical Cord Blood Transplantation
  • Experimental: Arm II (experimental)

    CONDITIONING REGIMEN: Patients receive the conditioning regimen chosen by the attending physician as in Standard of Care Arm.

    TRANSPLANT: Patients undergo single-unit or double-unit unmanipulated UCB transplant on day 0. Patients also undergo infusion of ex vivo-expanded cord blood progenitor cell infusion at least 4 hours after completion of UCB transplant.

    GVHD PROPHYLAXIS: Patients receive cyclosporine IV or PO and mycophenolate mofetil IV or PO as in Standard of Care Arm.

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cyclosporine
    • Procedure: Double-Unit Umbilical Cord Blood Transplantation
    • Procedure: Ex Vivo-Expanded Cord Blood Progenitor Cell Infusion
    • Drug: Fludarabine Phosphate
    • Other: Laboratory Biomarker Analysis
    • Drug: Mycophenolate Mofetil
    • Drug: Thiotepa
    • Radiation: Total-Body Irradiation
    • Procedure: Umbilical Cord Blood Transplantation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
160
Not Provided
April 30, 2018   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age criteria:

    • High dose TBI regimen: 6 months to =< 45 years
    • Middle intensity TBI regimen: 6 months to =< 65 years
    • Conditioning regimen selection should be based on the underlying disease, presence of minimal residual disease (MRD), age, co-morbidities, attending physician, and site preference; conditioning regimen will not require stratification of the randomization due to heterogeneity in the cohort of eligible patients.
  • Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia

    • All patients must have acute myeloid leukemia (AML) that is considered best treated by stem cell transplant by the referring physician and the attending transplant physician
    • All patients must be in complete remission (CR) as defined by < 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity >= 15% for age
    • 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
  • Acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia

    • High risk first complete remission (CR1) (for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed-lineage leukemia [MLL] rearrangements, hypodiploid); or high risk (HR) as defined by referring institution treatment protocol greater than 1 cycle to obtain CR; second complete remission (CR2) or greater
    • All patients must be in CR as defined by < 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity >= 15% for age
    • 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
  • Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in first chronic phase (CP1) patient must have failed or be intolerant to tyrosine kinase inhibitor therapy
  • Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
  • Karnofsky (>= 16 years old) >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-1
  • Lansky (< 16 years old) >= 60
  • Adults: calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL
  • Children (< 18 years old): calculated creatinine clearance must be > 60 mL/min
  • Total serum bilirubin must be < 3 mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis
  • Transaminases must be < 3 x the upper limit of normal per reference values of referring institution
  • Diffusing capacity of the lung for carbon monoxide (DLCO) corrected > 60% normal
  • For pediatric patients unable to perform pulmonary function tests, oxygen (O2) saturation > 92% on room air
  • May not be on supplemental oxygen
  • Left ventricular ejection fraction > 45% OR
  • Shortening fraction > 26%
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Uncontrolled viral or bacterial infection at the time of study enrollment
  • Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
  • History of human immunodeficiency virus (HIV) infection
  • Pregnant or breastfeeding
  • Prior myeloablative transplant containing full dose TBI (greater than 8 Gy)
  • Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiation of conditioning; diagnostic lumbar puncture is to be performed per protocol
  • Patients >= 45 years: comorbidity score of 5 or higher
Sexes Eligible for Study: All
6 Months to 65 Years   (Child, Adult)
No
United States
 
 
NCT01690520
2603.00
NCI-2012-01572 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2603
2603.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
P50HL110787 ( U.S. NIH Grant/Contract )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
  • National Cancer Institute (NCI)
  • National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Filippo Milano Fred Hutch/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
September 2017

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