Umbilical Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With Hematologic Disease

• ClinicalTrials.gov Identifier: NCT00719888
• Recruitment Status: Recruiting
• First Posted: July 22, 2008
• Last Update Posted: February 8, 2021
• Sponsor: Fred Hutchinson Cancer Research Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Fred Hutchinson Cancer Research Center

Tracking Information

• First Submitted Date: July 19, 2008
• First Posted Date: July 22, 2008
• Last Update Posted Date: February 8, 2021
• Actual Study Start Date: November 18, 2005
• Estimated Primary Completion Date: June 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 10, 2017)

Overall survival [ Time Frame: 1 year ]

A non-statistical comparison with historical controls will be made. Monitoring will take place separately for the single and double umbilical cord blood transplantation (UCBT) cohorts.

• Original Primary Outcome Measures (submitted: July 19, 2008): Overall survival at 1-year

Current Secondary Outcome Measures (submitted: May 13, 2019)

• Change in level of chimerism at multiple time points [ Time Frame: Baseline up to 2 years ]
  Cumulative incidence estimates will be used.
• Incidence of transplant-related mortality [ Time Frame: At 6 months ]
  Monitoring will take place separately for the single and double UCBT cohorts.
• Incidence of neutrophil engraftment [ Time Frame: At day 42 ]
  Monitoring will take place separately for the single and double UCBT cohorts.
• Incidence of platelet recovery [ Time Frame: At 6 months ]
  Monitoring will take place separately for the single and double UCBT cohorts.
• Incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) [ Time Frame: At day 100 ]
  Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. Monitoring will take place separately for the single and double UCBT cohorts.
• Incidence of chronic GVHD [ Time Frame: Up to 2 years ]
  Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.
• Incidence of clinically significant infections [ Time Frame: Up to 2 years ]
  Monitoring will take place separately for the single and double UCBT cohorts.
• Incidence of relapse [ Time Frame: Up to 2 years ]
  Cumulative incidence estimates will be used to summarize the time-to-event outcomes.
• Progression-free survival [ Time Frame: Up to 2 years ]
  A non-statistical comparison with historical controls will be made. Cumulative incidence estimates will be used to summarize the time-to-event outcomes. Monitoring will take place separately for the single and double UCBT cohorts.
• Single unit umbilical cord blood (UCB) transplants with historical controls [ Time Frame: Up to 2 years ]
  Single unit UCB transplants with historical controls will be compared.
• Single unit UCB transplants with double unit UCB transplants [ Time Frame: Up to 2 years ]
  Single unit UCB transplants with double unit UCB transplants will be compared.

Original Secondary Outcome Measures (submitted: July 19, 2008)

• Transplant-related mortality at 6 months
• Chimerism at multiple time points
• Neutrophil engraftment at day 42
• Platelet recovery at 6 months
• Acute graft-versus-host disease (GVHD)
• Chronic GVHD
• Clinically significant infections at multiple time points
• Relapse at 1 and 2 years
• Progression-free survival at 1 and 2 years
• Comparison of single unit UCB transplants with historical controls
• Comparison of single unit UCB transplants with double unit UCB transplants

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Umbilical Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With Hematologic Disease
• Official Title: Transplantation of Umbilical Cord Blood for Patients With Hematological Diseases With Cyclophosphamide/Fludarabine/Total Body Irradiation or Cyclophosphamide/Fludarabine/Thiotepa/Total Body Irradiation Myeloablative Preparative Regimen
• 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 disease. Giving chemotherapy, such as cyclophosphamide and fludarabine, and TBI before a donor umbilical cord blood transplant 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.

Detailed Description

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients 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 single- or double-unit UCBT on day 0.

ARM II: Patients 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 then undergo single- or double-unit UCBT on day 0.

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 6 months, 1 year, and 2 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Biphenotypic Leukemia
• Acute Myeloid Leukemia in Remission
• Ann Arbor Stage I Burkitt Lymphoma
• Ann Arbor Stage I Non-Hodgkin Lymphoma
• Ann Arbor Stage II Burkitt Lymphoma
• Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Lymphoblastic Lymphoma
• Mantle Cell Lymphoma
• Myelodysplastic Syndrome
• Myelofibrosis
• Plasma Cell Myeloma
• Prolymphocytic Leukemia
• Recurrent Chronic Lymphocytic Leukemia
• Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Recurrent Follicular Lymphoma
• Recurrent Lymphoplasmacytic Lymphoma
• Recurrent Marginal Zone Lymphoma
• Recurrent Small Lymphocytic Lymphoma
• Ann Arbor Stage II Non-Hodgkin Lymphoma
• Ann Arbor Stage III Burkitt Lymphoma
• Ann Arbor Stage III Non-Hodgkin Lymphoma
• Ann Arbor Stage IV Burkitt Lymphoma
• Ann Arbor Stage IV Non-Hodgkin Lymphoma
• High Risk Acute Myeloid Leukemia
• Refractory Anemia
• Hematopoietic and Lymphoid Cell Neoplasm

Intervention

• 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 and 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 UCBT
• Drug: Fludarabine
  Given IV
  Other Names:

  • 118218
  • Fluorovidarabine
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Mycophenolate Mofetil
  Given IV and PO
  Other Names:

  • Cellcept
  • MMF
• Radiation: Total-Body Irradiation
  Undergo high-dose or moderate-intensity TBI
  Other Names:

  • Total Body Irradiation
  • Whole-Body Irradiation
• Procedure: Umbilical Cord Blood Transplantation
  Undergo UCBT
  Other Names:

  • Cord Blood Transplantation
  • UCB transplantation
• Drug: Thiotepa
  Given IV
  Other Names:

  • 1,1',1"-phosphinothioylidynetrisaziridine
  • 1,1',1''-Phosphinothioyldynetrisaziridine
  • 52-24-4
  • 6396
  • Girostan
  • Triethylenethiophosphoramide

Study Arms

• Experimental: Treatment (myeloablative UCBT)

  Patients receive myeloablative conditioning comprising fludarabine IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose TBI BID on days -4 to -1. Patients then undergo single- or double-unit UCBT on day 0.

  Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine 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) 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.

  Interventions:

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

  Patients 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 QD on days -2 and -1. Patients then undergo single- or double-unit UCBT on day 0.

  Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine 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) 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.

  Interventions:

  • Drug: Cyclophosphamide
  • Drug: Cyclosporine
  • Procedure: Double-Unit Umbilical Cord Blood Transplantation
  • Drug: Fludarabine
  • Other: Laboratory Biomarker Analysis
  • Drug: Mycophenolate Mofetil
  • Radiation: Total-Body Irradiation
  • Procedure: Umbilical Cord Blood Transplantation
  • Drug: Thiotepa

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 7, 2018): 135
• Original Enrollment (submitted: July 19, 2008): 60
• Estimated Study Completion Date: June 1, 2025
• Estimated Primary Completion Date: June 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• GRAFT CRITERIA:

  • UCB units will be selected according to current umbilical cord blood graft selection algorithm; one or 2 UCB units may be used to achieve the required cell dose
  • The UCB graft is matched at 4-6 human leukocyte antigen (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
  • If 2 UCB units are required to reach the target cell dose, each unit must be a 4-6 antigen match to the recipient

• Age and Disease 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 minimum residual disease (MRD), age, co-morbidities, and attending physician

• Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia:

  • All patients must be in complete remission (CR) as defined by hematologic recovery and < 5% blasts by morphology/flow cytometry in a representative bone marrow sample with cellularity >= 15% for age; patients who do not have high-risk features (for example preceding myelodysplastic syndrome [MDS], high-risk cytogenetics, >= 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia or >= CR2) must be discussed with the principal investigator (PI) prior to enrollment and at the Patient Care Conference or equivalent group such as the pediatric leukemia board as an alternative
  • Patients in whom 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 PI prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with PI approval
• Very high risk pediatric/young adult patients with acute myeloid leukemia (AML): Patients =< 25 years, however, are eligible with (M2 marrow) with =< 25% blasts in marrow after having failed one or more cycles of chemotherapy; this group of patients will be analyzed separately

• Acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage leukemia:

  • 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 who do not have high-risk disease (high risk CR1, greater than one cycle to obtain CR or >= CR2) must be discussed with the PI prior to enrollment and at the Patient Care Conference or equivalent group such as the pediatric leukemia board as an alternative
  • Patients in whom 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 Ann Dahlberg prior to enrollment; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with PI approval
• Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate
• Advanced myelofibrosis
• Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
• Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade non-Hodgkin lymphoma (NHL) after initial therapy if stage III/IV in first partial response (PR1) or after progression if stage I/II < 1 year; stage III/IV patients are eligible after progression in CR/PR
• Chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma or follicular lymphoma that have progressed after at least two different prior therapies; patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant; these patients must be presented at primary care center (PCC) prior to enrollment, given potential competing eligibility on autotransplant protocols
• Mantle-cell lymphoma, prolymphocytic leukemia: Eligible after initial therapy in >= CR1 or >= PR1

• Large cell NHL > CR2/> second partial response (PR2):

  • Patients in CR2/PR2 with initial short remission (< 6 months) are eligible
  • These patients must be presented at PCC prior to enrollment, given potential competing eligibility on autotransplant protocols
• Multiple myeloma beyond PR2: Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or beta-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy
• Performance status score: Karnofsky (for adults) >= 70% or Eastern Cooperative Oncology Group (ECOG) 0-1 or Lansky (for children) >= 50%
• Creatinine < 2.0 mg/dL (for adults) or creatinine clearance > 60 ml/min (for children)
• 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
• Diffusion capacity for carbon monoxide corrected (DLCOcorr) > 50% normal or a pediatric patient who is unable to perform pulmonary function tests (PFTs) but has adequate pulmonary function
• Left ventricular ejection fraction > 45% or shortening fraction > 26%

Exclusion Criteria:

• Uncontrolled viral or bacterial infection at the time of study enrollment
• Active or recent (prior 6 month) invasive fungal infection without interdisciplinary (ID) consult and approval
• History of human immunodeficiency virus (HIV) infection
• Pregnant or breastfeeding
• Chemotherapy refractory large cell and high grade NHL (i.e., progressive disease after > 2 salvage regimens)
• Patients with history of prior myeloablative transplant containing full dose TBI (greater than 8 gray [Gy]) will not be eligible for Regimen A; however, they may still enroll on Regimen B if they otherwise meet inclusion and exclusion criteria
• Any prior myeloablative transplant within the last 6 months
• Patients >= 45 years: comorbidity score of 5 or higher
• Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy are not eligible for Regimen A

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 45 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Ann E. Dahlberg; 206-667-1959; adahlber@fredhutch.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00719888
• Other Study ID Numbers: 2010.00; NCI-2010-00190 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2010 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); RG2807002 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Fred Hutchinson Cancer Research Center
• Study Sponsor: Fred Hutchinson Cancer Research Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ann E. Dahlberg; Fred Hutch/University of Washington Cancer Consortium

• PRS Account: Fred Hutchinson Cancer Research Center
• Verification Date: February 2021