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Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Diseases

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.
 
ClinicalTrials.gov Identifier: NCT06013423
Recruitment Status : Not yet recruiting
First Posted : August 28, 2023
Last Update Posted : February 19, 2024
Sponsor:
Collaborator:
National Cord Blood Network
Information provided by (Responsible Party):
Fred Hutchinson Cancer Center

Tracking Information
First Submitted Date  ICMJE August 22, 2023
First Posted Date  ICMJE August 28, 2023
Last Update Posted Date February 19, 2024
Estimated Study Start Date  ICMJE March 15, 2024
Estimated Primary Completion Date October 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 22, 2023)
Overall survival [ Time Frame: At 1 year ]
Will be assessed after optimized cord blood transplant (CBT) in adults and children with hematologic malignancies. Will be calculated using the Kaplan-Meier method.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2023)
  • Cumulative incidence of neutrophil and platelet engraftment [ Time Frame: Up to 1 year ]
    Will be calculated within the competing risks framework considering death without neutrophil or platelet recovery, respectively, as completing events
  • Incidences of graft failure [ Time Frame: Up to 1 year ]
    Will be calculated within the competing risks framework considering death without engraftment before day 21 as a competing event.
  • Incidence of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) [ Time Frame: At day 100 ]
    Will be calculated within the competing risks framework considering relapse/ death without developing GVHD, death in the absence of relapse, and relapse as competing events, respectively.
  • Incidence of grade II-IV and III-IV aGVHD [ Time Frame: At day 180 ]
    Will be calculated within the competing risks framework considering relapse/ death without developing GVHD, death in the absence of relapse, and relapse as competing events, respectively.
  • Incidence of chronic graft-versus-host disease (cGVHD) [ Time Frame: At 1, 2 and 3 years ]
    Will be calculated within the competing risks framework considering relapse/ death without developing GVHD, death in the absence of relapse, and relapse as competing events, respectively.
  • Organ distribution of GVHD [ Time Frame: Up to 1 year ]
    Will be calculated within the competing risks framework considering death without neutrophil or platelet recovery, respectively, as completing events
  • Incidence of adverse events [ Time Frame: Up to 1 year ]
    Will be assessed using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0).
  • Time to immunosuppression cessation [ Time Frame: Up to 1 year ]
    Will be assessed using CTCAE v 5.0.
  • Pattern of donor chimerism [ Time Frame: Up to 1 year ]
    Will be assessed using CTCAE v 5.0.
  • Incidence of pre-engraftment syndrome (PES) [ Time Frame: Up to 1 year ]
    Will be assessed using CTCAE v 5.0.
  • Incidence of transplant related mortality (TRM) [ Time Frame: At 100 days, 6 months, 1 and 2 years ]
  • Incidence of relapse [ Time Frame: At 1, and 2 years after CBT ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Diseases
Official Title  ICMJE Optimized Cord Blood Transplantation for the Treatment of High-Risk Hematologic Malignancies in Adults and Pediatrics
Brief Summary This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine, and total-body irradiation (TBI) works in treating patients with hematologic diseases. Giving chemotherapy, such as cyclophosphamide, fludarabine and thiotepa, and TBI before a donor cord blood transplant (CBT) helps stop the growth of cancer and abnormal cells and helps 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening in patients with high-risk hematologic diseases.
Detailed Description

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients aged 6 months through 30 years old receive myeloablative conditioning comprising fludarabine intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose TBI twice daily (BID) on days -4 to -1. Patients then undergo UCBT on day 0. Patients undergo blood sample collection throughout the study. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and diagnostic imaging during screening and as clinically indicated on study. Patients also undergo blood sample collection and bone marrow aspirate during screening and on study.

ARM II: Patients aged 6 months through 65 years old receive myeloablative conditioning comprising fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days -5 and -4, and middle-intensity TBI once daily (QD) on days -2 and -1. Patients undergo ECHO or MUGA and diagnostic imaging during screening and as clinically indicated on study. Patients also undergo blood sample collection and bone marrow aspirate during screening and on study.

Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine orally (PO) (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) three times daily (TID) on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred > day 30) after engraftment if there continues to be no evidence of acute GVHD.

After completion of study treatment, patients are followed up at day 180, 1 year, and 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Leukemia of Ambiguous Lineage
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Hematopoietic and Lymphoid System Neoplasm
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Non-Hodgkin Lymphoma
  • Chronic Myeloid Leukemia, BCR-ABL1 Positive
Intervention  ICMJE
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other Names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Bone Marrow Aspirate
    Undergo bone marrow aspirate
    Other Names:
    • BONE MARROW, LIQUID
    • Human Bone Marrow Aspirate
  • Drug: Cyclophosphamide
    Receive 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
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
    • Asta B 518
    • B-518
    • WR-138719
  • Drug: Cyclosporine
    Receive IV or PO
    Other Names:
    • 27-400
    • Ciclosporin
    • CsA
    • Cyclosporin
    • Cyclosporin A
    • Cyclosporine Modified
    • Gengraf
    • Neoral
    • OL 27-400
    • Sandimmune
    • SangCya
  • Procedure: Diagnostic Imaging
    Undergo diagnostic imaging
    Other Name: Medical Imaging
  • Procedure: Echocardiography
    Undergo ECHO
    Other Name: EC
  • Drug: Fludarabine Phosphate
    Receive 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
  • Procedure: Multigated Acquisition Scan
    Undergo MUGA
    Other Names:
    • Blood Pool Scan
    • Equilibrium Radionuclide Angiography
    • Gated Blood Pool Imaging
    • Gated Heart Pool Scan
    • MUGA
    • MUGA Scan
    • Multi-Gated Acquisition Scan
    • Radionuclide Ventriculogram Scan
    • Radionuclide Ventriculography
    • RNVG
    • SYMA Scanning
    • Synchronized Multigated Acquisition Scanning
  • Drug: Mycophenolate Mofetil
    Receive IV
    Other Names:
    • CellCept
    • MMF
  • Other: Survey Administration
    Ancillary studies
  • Drug: Thiotepa
    Receive 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:
    • SCT_TBI
    • TBI
    • Total Body Irradiation
    • Whole Body
    • Whole Body Irradiation
    • Whole-Body Irradiation
  • Procedure: Umbilical Cord Blood Transplantation
    Undergo UCBT
    Other Names:
    • Cord Blood
    • Cord Blood Transplantation
    • UCB transplantation
    • UMBILICAL CORD BLOOD TRANSPLANT
Study Arms  ICMJE
  • Experimental: Arm I (myeloablative UCBT)
    See detailed description.
    Interventions:
    • Procedure: Biospecimen Collection
    • Procedure: Bone Marrow Aspirate
    • Drug: Cyclophosphamide
    • Drug: Cyclosporine
    • Procedure: Diagnostic Imaging
    • Procedure: Echocardiography
    • Drug: Fludarabine Phosphate
    • Procedure: Multigated Acquisition Scan
    • Drug: Mycophenolate Mofetil
    • Other: Survey Administration
    • Radiation: Total-Body Irradiation
    • Procedure: Umbilical Cord Blood Transplantation
  • Experimental: Arm II (myeloablative UCBT)
    See detailed description.
    Interventions:
    • Procedure: Biospecimen Collection
    • Procedure: Bone Marrow Aspirate
    • Drug: Cyclophosphamide
    • Drug: Cyclosporine
    • Procedure: Diagnostic Imaging
    • Procedure: Echocardiography
    • Drug: Fludarabine Phosphate
    • Procedure: Multigated Acquisition Scan
    • Drug: Mycophenolate Mofetil
    • Other: Survey Administration
    • Drug: Thiotepa
    • Radiation: Total-Body Irradiation
    • 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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: August 22, 2023)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 31, 2025
Estimated Primary Completion Date October 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients aged 6 months to =< 65 years at time of consent.
  • Acute myelogenous leukemia (AML):

    • Complete first remission (CR1), complete second remission (CR2) or greater (CR2+), must have < 5% marrow blasts at the time of transplant.
    • Patients in morphologic remission with persistent cytogenetic, flow cytometric, or molecular aberrations are eligible.
  • Acute lymphoblastic leukemia (ALL):

    • Complete first remission (CR1) at high risk for relapse such as any of the following:

      • Presence of any high-risk cytogenetic abnormalities such as t(9;22), t(1;19), t(4;11) or other MLL rearrangements (11q23) or other high-risk molecular abnormality.
      • Failure to achieve MRD- complete remission after induction therapy.
      • Persistence or recurrence of minimal residual disease on therapy.
      • Any patient unable to tolerate consolidation and/or maintenance chemotherapy as would have been deemed appropriate by the treating physician.
      • Other high-risk features not defined above.
    • Complete second remission (CR2) or greater (CR2+).

      • Note: ALL with less than 5% blasts at time of transplant but persistent cytogenetic, flow cytometric or molecular aberrations are eligible.
  • Other acute leukemias: Acute leukemias of ambiguous lineage or mixed phenotype with less than 5% blasts. Leukemias in morphologic remission with persistent cytogenetic, flow cytometric or molecular aberrations are eligible.
  • Chronic Myeloid Leukemia (CML): Excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to tyrosine kinase inhibitor therapy.
  • Myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) other than myelofibrosis:

    • MDS/MPD overlap syndromes without myelofibrosis.
    • MDS/ MPD patients must have less than 10% bone marrow myeloblasts and absolute neutrophil count (ANC) > 0.2 (growth factor supported if necessary) at transplant work-up.
  • Non-Hodgkin lymphoma (NHL) at high-risk of relapse or progression if not in remission:

    • Eligible patients with aggressive histology (such as, but not limited to, diffuse large B-cell NHL, mantle cell NHL, and T-cell histology) in CR by PET/CT imaging.
    • Eligible patients with indolent B-cell NHL (such as, but not limited to, follicular, small cell or marginal zone NHL) will have 2nd or subsequent progression with PR or CR by PET/CT imaging.
  • Blastic plasmacytoid dendritic cell neoplasm (BPDCN) in morphologic remission.
  • Only for adult patients, to prevent graft rejection, patients who received only non-lymphodepleting agents for their malignancy (hypomethylating agents, venetoclax, hydroxyurea, TKIs etc.), or patients who received lymphodepleting chemotherapy > 3 months prior to scheduled admission, may receive fludarabine 25 mg/m^2 daily x 3 days for lymphodepletion 14-42 days (aiming for 2-4 weeks) at the discretion of the principal investigator (PI).
  • For patients > 18 years old, Karnofsky score ≥ 70%. For patients =< 18 years old, Lansky score ≥ 50%.
  • Calculated creatinine clearance > 70 ml/min.
  • Bilirubin < 1.5 mg/dL (unless benign congenital hyperbilirubinemia or hemolysis).
  • Alanine transaminase (ALT) < 3 x upper limit of normal (ULN).
  • For patients > 18 years old, pulmonary function (spirometry and corrected diffusing capacity for carbon monoxide [DLCO]) > 60% predicted. For patients =< 18 years old, or any patient unable to perform pulmonary function tests, O2 saturation > 92% on room air.
  • Left ventricular ejection fraction > 50%.
  • Albumin > 3.0 g/dL.
  • For patients > 18 years old, Hematopoietic Cell Transplantation Comorbidity index (HCT-CI) =< 5.
  • UCB units will be selected according to current umbilical cord blood graft selection algorithm. One or two UCB units may be used to achieve the required cell dose.
  • The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. This may include 0-2 antigen mismatches at the A or B or DRB1 loci. Unit selection based on cryopreserved nucleated cell dose and HLA-A, B, DRB1 using intermediate resolution A, B antigen and DRB1 allele typing.

Exclusion Criteria:

  • Diagnosis of myelofibrosis or other malignancy with moderate-severe bone marrow fibrosis.
  • Patients persistent with central nervous system (CNS) involvement in cerebrospinal fluid (CSF) or CNS imaging at time of screening0
  • Prior checkpoint inhibitors/ blockade in the last 12 months.
  • Two prior stem cell transplants of any kind.
  • One prior autologous stem cell transplant within the preceding 12 months.
  • Prior allogeneic transplantation.
  • Prior involved field radiation therapy that would preclude safe delivery of 400cGy total body irradiation (TBI) in the opinion of radiation oncology.
  • Active and uncontrolled infection at time of transplantation.
  • HIV infection.
  • Inadequate performance status/ organ function.
  • Pregnancy or breast feeding.
  • Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, long-term follow-up, and research tests.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ann Dahlberg 206-667-1959 adahlber@fredhutch.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT06013423
Other Study ID Numbers  ICMJE RG1123652
NCI-2023-05598 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RG1123652 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Current Responsible Party Fred Hutchinson Cancer Center
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Fred Hutchinson Cancer Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE National Cord Blood Network
Investigators  ICMJE
Principal Investigator: Ann Dahlberg Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Center
Verification Date January 2024

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