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
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Accelerated Phase Chronic Myelogenous Leukemia Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome Adult Acute Lymphoblastic Leukemia in Remission Adult Acute Myeloid Leukemia in Remission Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Childhood Acute Lymphoblastic Leukemia in Remission Childhood Acute Myeloid Leukemia in Remission Childhood Chronic Myelogenous Leukemia Chronic Phase Chronic Myelogenous Leukemia de Novo Myelodysplastic Syndromes Previously Treated Myelodysplastic Syndromes Refractory Anemia Refractory Anemia With Excess Blasts Refractory Anemia With Excess Blasts in Transformation Relapsing Chronic Myelogenous Leukemia Secondary Acute Myeloid Leukemia |
Drug: fludarabine phosphate Drug: cyclophosphamide Radiation: total-body irradiation Procedure: ex vivo-expanded cord blood progenitor cell infusion Procedure: umbilical cord blood transplantation Procedure: double-unit umbilical cord blood transplantation Drug: cyclosporine Drug: mycophenolate mofetil Other: laboratory biomarker analysis |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | 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 |
- 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 ] [ Designated as safety issue: No ]The log-rank test will be used. 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 ] [ Designated as safety issue: No ]Groups will be compared using Gray's test.
- 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 ] [ Designated as safety issue: No ]Groups will be compared using Gray's test.
- Time to ANC greater than or equal to 100 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Time to ANC greater than or equal to 500 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Time to platelet engraftment (20k and 50k) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Duration of initial hospitalization [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Incidence of infectious complications [ Time Frame: Up to 100 days post-transplant ] [ Designated as safety issue: No ]
- Non-relapse mortality (NRM) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
- Incidence and severity of acute and chronic GVHD [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
- Infusional toxicity greater than or equal to grade 3 [ Time Frame: Day 0 (day of transplant) ] [ Designated as safety issue: Yes ]Toxicities will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
- Graft failure (primary and secondary) [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
- Kinetics of immune system recovery as measured by T and B cell subsets, T cell receptor excision circles (TREC), and T cell receptor (TCR) sequencing [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]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.
- Death without engraftment [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]Groups will be compared using Gray's test and log-rank test.
| Estimated Enrollment: | 160 |
| Study Start Date: | December 2012 |
| Estimated Primary Completion Date: | October 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Arm I (standard of care)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -8 to -6 and cyclophosphamide IV on days -7 to -6. Patients also undergo TBI BID on days -4 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) 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. |
Drug: fludarabine phosphate
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: umbilical cord blood transplantation
Undergo single-unit unmanipulated umbilical cord blood transplant
Other Names:
Procedure: double-unit umbilical cord blood transplantation
Undergo double-unit unmanipulated umbilical cord blood transplant
Drug: cyclosporine
Given IV
Other Names:
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
|
Experimental: Arm II (experimental)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV and cyclophosphamide IV, and undergo TBI 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 and mycophenolate mofetil IV or PO as in Standard of Care Arm. |
Drug: fludarabine phosphate
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: ex vivo-expanded cord blood progenitor cell infusion
Given IV
Procedure: umbilical cord blood transplantation
Undergo single-unit unmanipulated umbilical cord blood transplant
Other Names:
Procedure: double-unit umbilical cord blood transplantation
Undergo double-unit unmanipulated umbilical cord blood transplant
Drug: cyclosporine
Given IV
Other Names:
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Detailed Description:
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, day 200 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: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -8 to -6 and cyclophosphamide IV on days -7 to -6. Patients also undergo total-body irradiation (TBI) twice daily (BID) on days -4 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) 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 orally (PO) TID. Patients remain on MMF TID for a minimum of 30 days, and then may begin taper if there is no evidence of graft-versus-host disease (GVHD) and are well-engrafted from one donor unit.
Experimental Arm:
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV and cyclophosphamide IV, and undergo TBI 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 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.
Eligibility| Ages Eligible for Study: | 6 Months to 45 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
-
Acute myeloid leukemia
- High risk first complete remission (CR1) as evidenced by preceding myelodysplastic syndromes (MDS), high risk cytogenetics (for example, monosomy 5 or 7, or as defined by referring institution treatment protocol), >= 2 cycles to obtain complete remission (CR), erythroblastic or megakaryocytic leukemia; >= second complete remission (CR2)
- 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
-
Acute Lymphoblastic Leukemia
- High risk 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; 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 < 3mg/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)
- Any prior myeloablative transplant within the last 6 months
- 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
Contacts and LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT01690520
| United States, California | |
| City of Hope Medical Center | Not yet recruiting |
| Duarte, California, United States, 91010 | |
| Contact: Chatchada Karanes 626-359-8111 ext 62691 becomingapatient@coh.org | |
| Principal Investigator: Chatchada Karanes | |
| United States, Colorado | |
| University of Colorado | Recruiting |
| Denver, Colorado, United States, 80217-3364 | |
| Contact: Jonathan A. Gutman 720-848-0644 | |
| Principal Investigator: Jonathan A. Gutman | |
| United States, Massachusetts | |
| Dana-Farber Harvard Cancer Center | Not yet recruiting |
| Boston, Massachusetts, United States, 02115 | |
| Contact: Christine N. Duncan 617-632-6255 | |
| Principal Investigator: Christine N. Duncan | |
| United States, North Carolina | |
| Duke University Medical Center | Not yet recruiting |
| Durham, North Carolina, United States, 27710 | |
| Contact: Joanne Kurtzberg 919-668-1100 | |
| Principal Investigator: Joanne Kurtzberg | |
| United States, Ohio | |
| Cleveland Clinic Foundation | Not yet recruiting |
| Cleveland, Ohio, United States, 44195 | |
| Contact: Rabi Hanna 216-444-0663 | |
| Principal Investigator: Rabi Hanna | |
| United States, Tennessee | |
| Vanderbilt-Ingram Cancer Center | Recruiting |
| Nashville, Tennessee, United States, 37232 | |
| Contact: Haydar A. Frangoul 615-936-1762 | |
| Principal Investigator: Haydar A. Frangoul | |
| 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 | |
| Principal Investigator: Colleen Delaney | |
| 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: | NCT01690520 History of Changes |
| Other Study ID Numbers: | 2603.00, NCI-2012-01572, 2603, 2603.00, P30CA015704, P50HL110787 |
| Study First Received: | September 19, 2012 |
| Last Updated: | October 9, 2014 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Anemia Anemia, Refractory Anemia, Refractory, with Excess of Blasts Leukemia Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid Leukemia, Myeloid, Accelerated Phase Leukemia, Myeloid, Acute Leukemia, Myeloid, Chronic-Phase Myelodysplastic Syndromes Precursor Cell Lymphoblastic Leukemia-Lymphoma Preleukemia Syndrome 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 Cyclophosphamide Cyclosporine Cyclosporins Fludarabine |
ClinicalTrials.gov processed this record on March 01, 2015