Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Diseases
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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 |
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Recruitment Status :
Not yet recruiting
First Posted : August 28, 2023
Last Update Posted : August 28, 2023
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Sponsor:
Fred Hutchinson Cancer Center
Collaborator:
National Cord Blood Network
Information provided by (Responsible Party):
Fred Hutchinson Cancer Center
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | 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 | Phase 2 |
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 : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 54 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Optimized Cord Blood Transplantation for the Treatment of High-Risk Hematologic Malignancies in Adults and Pediatrics |
| Estimated Study Start Date : | January 1, 2024 |
| Estimated Primary Completion Date : | October 31, 2024 |
| Estimated Study Completion Date : | October 31, 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Blood Disorders
Genetic and Rare Diseases Information Center resources:
Lymphosarcoma
Chronic Myeloproliferative Disorders
Myeloid Leukemia
Acute Myeloid Leukemia
Acute Non Lymphoblastic Leukemia
Myelodysplastic Syndromes
Acute Lymphoblastic Leukemia
Lymphoblastic Lymphoma
Acute Graft Versus Host Disease
Dendritic Cell Tumor
Acute Leukemia of Ambiguous Lineage
Blastic Plasmacytoid Dendritic Cell
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (myeloablative UCBT)
See detailed description.
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Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
Procedure: Bone Marrow Aspirate Undergo bone marrow aspirate
Other Names:
Drug: Cyclophosphamide Receive IV
Other Names:
Drug: Cyclosporine Receive IV or PO
Other Names:
Procedure: Diagnostic Imaging Undergo diagnostic imaging
Other Name: Medical Imaging Procedure: Echocardiography Undergo ECHO
Other Name: EC Drug: Fludarabine Phosphate Receive IV
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Mycophenolate Mofetil Receive IV
Other Names:
Other: Survey Administration Ancillary studies Radiation: Total-Body Irradiation Undergo high-dose or middle-intensity TBI
Other Names:
Procedure: Umbilical Cord Blood Transplantation Undergo UCBT
Other Names:
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Experimental: Arm II (myeloablative UCBT)
See detailed description.
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Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
Procedure: Bone Marrow Aspirate Undergo bone marrow aspirate
Other Names:
Drug: Cyclophosphamide Receive IV
Other Names:
Drug: Cyclosporine Receive IV or PO
Other Names:
Procedure: Diagnostic Imaging Undergo diagnostic imaging
Other Name: Medical Imaging Procedure: Echocardiography Undergo ECHO
Other Name: EC Drug: Fludarabine Phosphate Receive IV
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Mycophenolate Mofetil Receive IV
Other Names:
Other: Survey Administration Ancillary studies Drug: Thiotepa Receive IV
Other Names:
Radiation: Total-Body Irradiation Undergo high-dose or middle-intensity TBI
Other Names:
Procedure: Umbilical Cord Blood Transplantation Undergo UCBT
Other Names:
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Primary Outcome Measures :
- 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.
Secondary Outcome Measures :
- 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 ]
Information from the National Library of Medicine
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| Ages Eligible for Study: | 6 Months to 65 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patients aged 6 months to =< 65 years at time of consent.
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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.
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Acute lymphoblastic leukemia (ALL):
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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.
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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.
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- 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.
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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.
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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 equal or greater than 70%. For patients =< 18 years old, Lansky score equal to or greater than 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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06013423
Contacts
| Contact: Ann Dahlberg | 206-667-1959 | adahlber@fredhutch.org |
Locations
| United States, Washington | |
| Fred Hutch/University of Washington Cancer Consortium | |
| Seattle, Washington, United States, 98109 | |
| Contact: Ann Dahlberg 206-667-1959 adahlber@fredhutch.org | |
| Principal Investigator: Ann Dahlberg | |
Sponsors and Collaborators
Fred Hutchinson Cancer Center
National Cord Blood Network
Investigators
| Principal Investigator: | Ann Dahlberg | Fred Hutch/University of Washington Cancer Consortium |
| Responsible Party: | Fred Hutchinson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT06013423 |
| Other Study ID Numbers: |
RG1123652 NCI-2023-05598 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) RG1123652 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) |
| First Posted: | August 28, 2023 Key Record Dates |
| Last Update Posted: | August 28, 2023 |
| Last Verified: | August 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Leukemia Neoplasms Precursor Cell Lymphoblastic Leukemia-Lymphoma Myelodysplastic Syndromes Myeloproliferative Disorders Acute Disease Neoplasms by Histologic Type Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Bone Marrow Diseases Hematologic Diseases Leukemia, Lymphoid Disease Attributes |
Pathologic Processes Cyclosporine Mycophenolic Acid Cyclophosphamide Thiotepa Fludarabine Fludarabine phosphate Cyclosporins Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action |