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出境医 / 临床实验 / Graft Versus Host Disease-Reduction Strategies for Donor Blood Stem Cell Transplant Patients With Acute Leukemia

Graft Versus Host Disease-Reduction Strategies for Donor Blood Stem Cell Transplant Patients With Acute Leukemia

Study Description
Brief Summary:
This phase II trial investigates three strategies and how well they work for the reduction of graft versus host disease in patients with acute leukemia in remission. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also 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. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

Condition or disease Intervention/treatment Phase
Acute Biphenotypic Leukemia Acute Leukemia of Ambiguous Lineage Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Undifferentiated Leukemia Blastic Plasmacytoid Dendritic Cell Neoplasm Lymphoblastic Lymphoma Mixed Phenotype Acute Leukemia Acute Leukemia Hematopoietic and Lymphoid Cell Neoplasm Radiation: Total-Body Irradiation Drug: Thiotepa Drug: Fludarabine Drug: Tacrolimus Biological: Allogeneic CD34+-enriched and CD45RA-depleted PBSCs Drug: Methotrexate Drug: Cyclophosphamide Biological: Peripheral Blood Stem Cell Drug: Cyclosporine Drug: Sirolimus Phase 2

Detailed Description:

OUTLINE:

Patients are randomized to 1 of 3 arms.

ARM A: Patients undergo total-body irradiation (TBI) twice daily (BID) on days -10 to -7, and receive thiotepa intravenously (IV) over 3 hours on days -6 and -5, fludarabine IV over 30 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).

ARM C: Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 hour on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).

ARM D: Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).

After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 56, 80, 180, and 270 and at 1, 1.5, and 2 years.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Randomized Controlled Trial Comparing GVHD-Reduction Strategies for Allogeneic Peripheral Blood Transplantation (PBSCT) for Patients With Acute Leukemia: Selective Depletion of CD45RA+ Naïve T Cells (TND) vs.Post-Transplantation Cyclophosphamide (PTCy) vs. Tacrolimus and Methotrexate (TacMTX) PBSCT
Actual Study Start Date : November 19, 2019
Estimated Primary Completion Date : August 1, 2023
Estimated Study Completion Date : August 1, 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: Arm A (TnD)
Patients undergo TBI BID on days -10 to -7, and receive thiotepa IV over 3 hours on days -6 and -5, fludarabine IV over 30 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation
  • TBI
  • Whole Body Irradiation
  • SCT_TBI
  • Total-Body Irradiation Prior to Stem Cell Transplant

Drug: Thiotepa
Given IV
Other Names:
  • Oncotiotepa
  • STEPA
  • Tepadina
  • TESPA
  • Tespamin
  • Tespamine
  • Thio-Tepa
  • Thiofosfamide
  • Thiofozil
  • Thiophosphamide
  • Thiophosphoramide
  • Thiotef
  • Triethylene
  • Triethylenethiophosphoramide

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Drug: Tacrolimus
Given IV
Other Names:
  • Prograf
  • Protopic

Biological: Allogeneic CD34+-enriched and CD45RA-depleted PBSCs
Given IV
Other Names:
  • Allogeneic TN-depleted CD34-preserved PBSCs
  • Allogeneic TND- CD34+ PBSCs
  • Donor-derived TN Cell Depleted CD34-enriched PBSCs
  • Naive T-cell Depleted CD34+ Allogeneic Peripheral Blood Stem Cells

Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • Emthexat
  • Emtexate
  • Farmitrexat
  • Methotrexate LPF
  • Methylaminopterin
  • Methotrexatum
  • Metotrexato

Drug: Cyclosporine
Given IV
Other Names:
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Cyclosporine Modified
  • Gengraf
  • Neoral
  • Sandimmune
  • SangCya

Drug: Sirolimus
Given IV
Other Names:
  • RAPA
  • Rapamune
  • rapamycin
  • SILA 9268A
  • WY-090217

Experimental: Arm C (PTCy, tacrolimus)
Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 hour on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation
  • TBI
  • Whole Body Irradiation
  • SCT_TBI
  • Total-Body Irradiation Prior to Stem Cell Transplant

Drug: Tacrolimus
Given IV
Other Names:
  • Prograf
  • Protopic

Drug: Cyclophosphamide
Given IV
Other Names:
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Claphene
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cytophosphan

Biological: Peripheral Blood Stem Cell
Given IV
Other Names:
  • PBSC
  • Peripheral Blood Stem Cells
  • peripheral stem cell
  • Peripheral Stem Cells

Drug: Cyclosporine
Given IV
Other Names:
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Cyclosporine Modified
  • Gengraf
  • Neoral
  • Sandimmune
  • SangCya

Drug: Sirolimus
Given IV
Other Names:
  • RAPA
  • Rapamune
  • rapamycin
  • SILA 9268A
  • WY-090217

Experimental: Arm D (tacrolimus, methotrexate)
Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation
  • TBI
  • Whole Body Irradiation
  • SCT_TBI
  • Total-Body Irradiation Prior to Stem Cell Transplant

Drug: Tacrolimus
Given IV
Other Names:
  • Prograf
  • Protopic

Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • Emthexat
  • Emtexate
  • Farmitrexat
  • Methotrexate LPF
  • Methylaminopterin
  • Methotrexatum
  • Metotrexato

Drug: Cyclophosphamide
Given IV
Other Names:
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Claphene
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cytophosphan

Biological: Peripheral Blood Stem Cell
Given IV
Other Names:
  • PBSC
  • Peripheral Blood Stem Cells
  • peripheral stem cell
  • Peripheral Stem Cells

Drug: Cyclosporine
Given IV
Other Names:
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Cyclosporine Modified
  • Gengraf
  • Neoral
  • Sandimmune
  • SangCya

Drug: Sirolimus
Given IV
Other Names:
  • RAPA
  • Rapamune
  • rapamycin
  • SILA 9268A
  • WY-090217

Outcome Measures
Primary Outcome Measures :
  1. Graft versus host disease (GVHD)-free relapse-free survival (RFS) [ Time Frame: At 2 years ]
    Will be defined as survival-free of a history of: a) relapse after hematopoietic cell transplantation (HCT), b) grade III-IV acute GVHD after HCT, moderate or severe chronic GVHD meeting National Institutes of Health (NIH) criteria and requiring systemic pharmacologic immunosuppression for treatment of GVHD. RFS distribution will be estimated for each arm by the Kaplan-Meier curve, starting from the time of HCT. A 90% confidence interval (CI) will be constructed at 1 and 2-year post-HCT timepoints.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: At 2 years ]
    Death will be considered as the event, and the OS distribution will be estimated for each group by the Kaplan-Meier method, starting from the time of HCT. A 90% CI will be constructed at the 1 and 2-year post-HCT time points.

  2. Relapse [ Time Frame: At 2 years ]
    Will be defined as recurrence of leukemia (>= 5% leukemic blasts by flow or morphology) in bone marrow, circulating leukemic blasts or extramedullary disease (extramedullary disease definite i.e. proven by biopsy or probably based on clinical assessment if biopsy not feasible). Lower levels of leukemia in bone marrow or blood will be recorded and reported as 'measurable residual disease' but will not be considered relapse.

  3. Proportion of patients alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD [ Time Frame: At 3, 6, 9, 12, 15, 18, 21, 24 months post HCT ]
  4. Graft rejection or irreversible graft failure (> 14 days duration) [ Time Frame: At 2 years ]
    Will be operationally defined as failure to achieve an absolute neutrophil count (ANC) >= 0.5 x 10^9/L before death or second HCT, or decrease to ANC < 0.1 x 10^9/L for 14 consecutive days (date of graft failure defined as the 14th day) after an established donor graft despite daily administration of granulocyte colony-stimulating factor (subcutaneously or intravenously) and =< 20% bone marrow cellularity on bone marrow aspirate or biopsy any time in the first 2 years following HCT. If the delay or reduction in ANC is due to relapse (as determined by histopathology, flow cytometry or cytogenetic or molecular studies) this will not be considered graft failure. If a patient dies from organ toxicity and/or infection prior to day 28 without ANC >= 0.5 x 10^9/L this will not be considered graft failure.

  5. Incidence of chronic GVHD [ Time Frame: Up to 2 years ]
    Will be defined and graded based on NIH criteria and graded operationally as the occurrence of compatible symptoms.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients who are considered appropriate candidates for myeloablative, TBI-containing allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses:

    • Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
    • Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
    • Other acute leukemia or related neoplasm (including but not limited to 'mixed phenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
  • Patient age 1 -50 years old (inclusive) at the time of informed consent
  • Patient with an HLA-matched (HLA-A, B, C, DRB1, and DQB1 matched) related or unrelated donor capable of donating PBSC.
  • Recipient informed consent/assent and/or legal guardian permission must be obtained.
  • DONOR: HLA-matched related and unrelated donors (HLA-A, B, C, DRB1 and DQB1 matched based on high-resolution typing).
  • DONOR: >= 18 years old.
  • DONOR: Willing to donate PBSC.
  • DONOR: Matched related donors:

    • Must give informed consent using the related donor informed consent form.
    • Must meet institutional donor eligibility criteria or be ineligible with statement that the donor is a first or second degree relative (exception 21 Code of Federal Regulations [CFR] 1271.65(b)(i)).
  • DONOR: Matched unrelated donors:

    • Must consent according to the applicable National Marrow Donor Program (NMDP) donor regulatory requirements.
    • Must meet eligibility criteria as defined by the NMDP or be ineligible with statement of urgent medical need (exception 21 CFR 1271.65(b)(iii)).

Exclusion Criteria:

  • Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation. A patient may have a history of CNS disease. However, any CNS disease must be cleared by the end of the pre-conditioning evaluation time frame. If CNS disease is identified on cerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparative regimen a repeat CSF evaluation must be performed and show no evidence of disease in order for the patient to be eligible for the protocol.
  • Patients on other experimental protocols for prevention of GVHD.
  • Patient weight:

    • Patients with HLA-matched related donors will be excluded if they weigh >= 100 kg.
    • Patients with HLA-matched unrelated donors will be excluded if they weigh >= 100 kg and must be discussed with the Fred Hutch protocol principal investigator (PI) if they weigh >= 80 kg.
  • Patients who are positive for human immunodeficiency virus (HIV)-1, HIV-2, human T-cell lymphotropic virus (HTLV)1 or HTLV2.
  • Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician; i.e. patients with active infections require infectious disease consultation and documentation by the infectious disease team that myeloablative HCT is not considered to be contraindicated. Upper respiratory tract infection is not considered to represent an uncontrolled infection in this context.
  • Patients with organ dysfunction, including:

    • Renal insufficiency (creatinine > 1.5 mg/dl) at the time of evaluation for the protocol. Patients with a known history of creatinine > 1.5 mg/dl or a current serum creatinine above the normal range for age must have a current creatinine clearance of > 60 ml/min/1.73 m^2 (measured by 24-hr urine specimen or nuclear glomerular filtration rate [GFR]).
    • Left ventricular ejection fraction < 45%.
    • Carbon monoxide diffusing capability (DLCO) corrected < 60%. Patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air.
    • Liver function abnormality. Patients who have liver function test (LFT)s (specifically, total bilirubin, aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician unless there is a clear precipitating factor (such as an azole, MTX, trimethoprim-sulfamethoxazole, or another drug). If the GI physician considers that HCT on the protocol is contraindicated, that patient will be excluded from the protocol. Patients with Gilbert's syndrome and no other known liver function abnormality or with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol.
  • Patients who have received previous myeloablative allogeneic or autologous transplantation.
  • Patients with a life expectancy < 12 months from co-existing disease other than the leukemia.
  • Patients who are pregnant or breast-feeding.
  • Patients of childbearing age who are presumed to be fertile and are unwilling to use an effective birth control method or refrain from sexual intercourse during and for 12 months post-HCT.
  • Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI.
  • Patients with a known hypersensitivity to tacrolimus, MTX or thymoglobulin
  • Patients who have received checkpoint inhibitors within three months of transplantation unless an exception is made by the PI
  • DONOR: Donors who are HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection. Test must be performed using Food and Drug Administration (FDA) licensed, cleared, and approved test kits (serological and/or nucleic acid amplification test [NAT] and/or other approved testing) in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory.
  • DONOR: Unrelated donors donating outside of the United States of America (USA).
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Marie Bleakley 206-667-6572 mbleakle@fredhutch.org

Locations
Layout table for location information
United States, Florida
Moffitt Cancer Center Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Taiga Nishihori    813-745-4673    taiga.nishihori@moffitt.org   
Principal Investigator: Taiga Nishihori         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Alison Sehgal    412-623-2861    sehgalar@upmc.edu   
Principal Investigator: Alison Sehgal         
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Marie Bleakley    206-667-6572    mbleakle@fredhutch.org   
Principal Investigator: Marie Bleakley         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Marie Bleakley Fred Hutch/University of Washington Cancer Consortium
Tracking Information
First Submitted Date  ICMJE May 29, 2019
First Posted Date  ICMJE May 31, 2019
Last Update Posted Date April 29, 2021
Actual Study Start Date  ICMJE November 19, 2019
Estimated Primary Completion Date August 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
Graft versus host disease (GVHD)-free relapse-free survival (RFS) [ Time Frame: At 2 years ]
Will be defined as survival-free of a history of: a) relapse after hematopoietic cell transplantation (HCT), b) grade III-IV acute GVHD after HCT, moderate or severe chronic GVHD meeting National Institutes of Health (NIH) criteria and requiring systemic pharmacologic immunosuppression for treatment of GVHD. RFS distribution will be estimated for each arm by the Kaplan-Meier curve, starting from the time of HCT. A 90% confidence interval (CI) will be constructed at 1 and 2-year post-HCT timepoints.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2021)
  • Overall survival (OS) [ Time Frame: At 2 years ]
    Death will be considered as the event, and the OS distribution will be estimated for each group by the Kaplan-Meier method, starting from the time of HCT. A 90% CI will be constructed at the 1 and 2-year post-HCT time points.
  • Relapse [ Time Frame: At 2 years ]
    Will be defined as recurrence of leukemia (>= 5% leukemic blasts by flow or morphology) in bone marrow, circulating leukemic blasts or extramedullary disease (extramedullary disease definite i.e. proven by biopsy or probably based on clinical assessment if biopsy not feasible). Lower levels of leukemia in bone marrow or blood will be recorded and reported as 'measurable residual disease' but will not be considered relapse.
  • Proportion of patients alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD [ Time Frame: At 3, 6, 9, 12, 15, 18, 21, 24 months post HCT ]
  • Graft rejection or irreversible graft failure (> 14 days duration) [ Time Frame: At 2 years ]
    Will be operationally defined as failure to achieve an absolute neutrophil count (ANC) >= 0.5 x 10^9/L before death or second HCT, or decrease to ANC < 0.1 x 10^9/L for 14 consecutive days (date of graft failure defined as the 14th day) after an established donor graft despite daily administration of granulocyte colony-stimulating factor (subcutaneously or intravenously) and =< 20% bone marrow cellularity on bone marrow aspirate or biopsy any time in the first 2 years following HCT. If the delay or reduction in ANC is due to relapse (as determined by histopathology, flow cytometry or cytogenetic or molecular studies) this will not be considered graft failure. If a patient dies from organ toxicity and/or infection prior to day 28 without ANC >= 0.5 x 10^9/L this will not be considered graft failure.
  • Incidence of chronic GVHD [ Time Frame: Up to 2 years ]
    Will be defined and graded based on NIH criteria and graded operationally as the occurrence of compatible symptoms.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Overall survival (OS) [ Time Frame: At 2 years ]
    Death will be considered as the event, and the OS distribution will be estimated for each group by the Kaplan-Meier method, starting from the time of HCT. A 90% CI will be constructed at the 1 and 2-year post-HCT time points.
  • Relapse [ Time Frame: At 2 years ]
    Will be defined as recurrence of leukemia (>= 5% leukemic blasts by flow or morphology) in bone marrow, circulating leukemic blasts or extramedullary disease (extramedullary disease definite i.e. proven by biopsy or probably based on clinical assessment if biopsy not feasible). Lower levels of leukemia in bone marrow or blood will be recorded and reported as 'measurable residual disease' but will not be considered relapse.
  • Proportion of patients alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD [ Time Frame: At 3, 6, 9, 12, 15, 18, 21, 24 months post HCT ]
  • Graft rejection or graft failure (> 14 days duration) [ Time Frame: At 2 years ]
    Will be operationally defined as failure to achieve an absolute neutrophil count (ANC) >= 0.5 x 10^9/L before death or second HCT, or decrease to ANC < 0.1 x 10^9/L for 14 consecutive days (date of graft failure defined as the 14th day) after an established donor graft despite daily administration of granulocyte colony-stimulating factor (subcutaneously or intravenously) and =< 20% bone marrow cellularity on bone marrow aspirate or biopsy any time in the first 2 years following HCT. If the delay or reduction in ANC is due to relapse (as determined by histopathology, flow cytometry or cytogenetic or molecular studies) this will not be considered graft failure. If a patient dies from organ toxicity and/or infection prior to day 28 without ANC >= 0.5 x 10^9/L this will not be considered graft failure.
  • Incidence of chronic GVHD [ Time Frame: Up to 3 years ]
    Will be defined and graded based on NIH criteria and graded operationally as the occurrence of compatible symptoms.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Graft Versus Host Disease-Reduction Strategies for Donor Blood Stem Cell Transplant Patients With Acute Leukemia
Official Title  ICMJE A Phase II Randomized Controlled Trial Comparing GVHD-Reduction Strategies for Allogeneic Peripheral Blood Transplantation (PBSCT) for Patients With Acute Leukemia: Selective Depletion of CD45RA+ Naïve T Cells (TND) vs.Post-Transplantation Cyclophosphamide (PTCy) vs. Tacrolimus and Methotrexate (TacMTX) PBSCT
Brief Summary This phase II trial investigates three strategies and how well they work for the reduction of graft versus host disease in patients with acute leukemia in remission. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also 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. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.
Detailed Description

OUTLINE:

Patients are randomized to 1 of 3 arms.

ARM A: Patients undergo total-body irradiation (TBI) twice daily (BID) on days -10 to -7, and receive thiotepa intravenously (IV) over 3 hours on days -6 and -5, fludarabine IV over 30 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).

ARM C: Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 hour on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).

ARM D: Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).

After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 56, 80, 180, and 270 and at 1, 1.5, and 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Biphenotypic Leukemia
  • Acute Leukemia of Ambiguous Lineage
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Acute Undifferentiated Leukemia
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Lymphoblastic Lymphoma
  • Mixed Phenotype Acute Leukemia
  • Acute Leukemia
  • Hematopoietic and Lymphoid Cell Neoplasm
Intervention  ICMJE
  • Radiation: Total-Body Irradiation
    Undergo TBI
    Other Names:
    • Total Body Irradiation
    • Whole-Body Irradiation
    • TBI
    • Whole Body Irradiation
    • SCT_TBI
    • Total-Body Irradiation Prior to Stem Cell Transplant
  • Drug: Thiotepa
    Given IV
    Other Names:
    • Oncotiotepa
    • STEPA
    • Tepadina
    • TESPA
    • Tespamin
    • Tespamine
    • Thio-Tepa
    • Thiofosfamide
    • Thiofozil
    • Thiophosphamide
    • Thiophosphoramide
    • Thiotef
    • Triethylene
    • Triethylenethiophosphoramide
  • Drug: Fludarabine
    Given IV
    Other Name: Fluradosa
  • Drug: Tacrolimus
    Given IV
    Other Names:
    • Prograf
    • Protopic
  • Biological: Allogeneic CD34+-enriched and CD45RA-depleted PBSCs
    Given IV
    Other Names:
    • Allogeneic TN-depleted CD34-preserved PBSCs
    • Allogeneic TND- CD34+ PBSCs
    • Donor-derived TN Cell Depleted CD34-enriched PBSCs
    • Naive T-cell Depleted CD34+ Allogeneic Peripheral Blood Stem Cells
  • Drug: Methotrexate
    Given IV
    Other Names:
    • Abitrexate
    • Alpha-Methopterin
    • Amethopterin
    • Brimexate
    • Emthexat
    • Emtexate
    • Farmitrexat
    • Methotrexate LPF
    • Methylaminopterin
    • Methotrexatum
    • Metotrexato
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Claphene
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cytophosphan
  • Biological: Peripheral Blood Stem Cell
    Given IV
    Other Names:
    • PBSC
    • Peripheral Blood Stem Cells
    • peripheral stem cell
    • Peripheral Stem Cells
  • Drug: Cyclosporine
    Given IV
    Other Names:
    • Ciclosporin
    • CsA
    • Cyclosporin
    • Cyclosporin A
    • Cyclosporine Modified
    • Gengraf
    • Neoral
    • Sandimmune
    • SangCya
  • Drug: Sirolimus
    Given IV
    Other Names:
    • RAPA
    • Rapamune
    • rapamycin
    • SILA 9268A
    • WY-090217
Study Arms  ICMJE
  • Experimental: Arm A (TnD)
    Patients undergo TBI BID on days -10 to -7, and receive thiotepa IV over 3 hours on days -6 and -5, fludarabine IV over 30 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
    Interventions:
    • Radiation: Total-Body Irradiation
    • Drug: Thiotepa
    • Drug: Fludarabine
    • Drug: Tacrolimus
    • Biological: Allogeneic CD34+-enriched and CD45RA-depleted PBSCs
    • Drug: Methotrexate
    • Drug: Cyclosporine
    • Drug: Sirolimus
  • Experimental: Arm C (PTCy, tacrolimus)
    Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 hour on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
    Interventions:
    • Radiation: Total-Body Irradiation
    • Drug: Tacrolimus
    • Drug: Cyclophosphamide
    • Biological: Peripheral Blood Stem Cell
    • Drug: Cyclosporine
    • Drug: Sirolimus
  • Experimental: Arm D (tacrolimus, methotrexate)
    Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid).
    Interventions:
    • Radiation: Total-Body Irradiation
    • Drug: Tacrolimus
    • Drug: Methotrexate
    • Drug: Cyclophosphamide
    • Biological: Peripheral Blood Stem Cell
    • Drug: Cyclosporine
    • Drug: Sirolimus
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 27, 2021)
120
Original Estimated Enrollment  ICMJE
 (submitted: May 29, 2019)
160
Estimated Study Completion Date  ICMJE August 1, 2024
Estimated Primary Completion Date August 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients who are considered appropriate candidates for myeloablative, TBI-containing allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses:

    • Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
    • Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
    • Other acute leukemia or related neoplasm (including but not limited to 'mixed phenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
  • Patient age 1 -50 years old (inclusive) at the time of informed consent
  • Patient with an HLA-matched (HLA-A, B, C, DRB1, and DQB1 matched) related or unrelated donor capable of donating PBSC.
  • Recipient informed consent/assent and/or legal guardian permission must be obtained.
  • DONOR: HLA-matched related and unrelated donors (HLA-A, B, C, DRB1 and DQB1 matched based on high-resolution typing).
  • DONOR: >= 18 years old.
  • DONOR: Willing to donate PBSC.
  • DONOR: Matched related donors:

    • Must give informed consent using the related donor informed consent form.
    • Must meet institutional donor eligibility criteria or be ineligible with statement that the donor is a first or second degree relative (exception 21 Code of Federal Regulations [CFR] 1271.65(b)(i)).
  • DONOR: Matched unrelated donors:

    • Must consent according to the applicable National Marrow Donor Program (NMDP) donor regulatory requirements.
    • Must meet eligibility criteria as defined by the NMDP or be ineligible with statement of urgent medical need (exception 21 CFR 1271.65(b)(iii)).

Exclusion Criteria:

  • Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation. A patient may have a history of CNS disease. However, any CNS disease must be cleared by the end of the pre-conditioning evaluation time frame. If CNS disease is identified on cerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparative regimen a repeat CSF evaluation must be performed and show no evidence of disease in order for the patient to be eligible for the protocol.
  • Patients on other experimental protocols for prevention of GVHD.
  • Patient weight:

    • Patients with HLA-matched related donors will be excluded if they weigh >= 100 kg.
    • Patients with HLA-matched unrelated donors will be excluded if they weigh >= 100 kg and must be discussed with the Fred Hutch protocol principal investigator (PI) if they weigh >= 80 kg.
  • Patients who are positive for human immunodeficiency virus (HIV)-1, HIV-2, human T-cell lymphotropic virus (HTLV)1 or HTLV2.
  • Patients with uncontrolled infections for whom myeloablative HCT is considered contraindicated by the consulting infectious disease physician; i.e. patients with active infections require infectious disease consultation and documentation by the infectious disease team that myeloablative HCT is not considered to be contraindicated. Upper respiratory tract infection is not considered to represent an uncontrolled infection in this context.
  • Patients with organ dysfunction, including:

    • Renal insufficiency (creatinine > 1.5 mg/dl) at the time of evaluation for the protocol. Patients with a known history of creatinine > 1.5 mg/dl or a current serum creatinine above the normal range for age must have a current creatinine clearance of > 60 ml/min/1.73 m^2 (measured by 24-hr urine specimen or nuclear glomerular filtration rate [GFR]).
    • Left ventricular ejection fraction < 45%.
    • Carbon monoxide diffusing capability (DLCO) corrected < 60%. Patients who are unable to perform pulmonary function tests (for example, due to young age and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air.
    • Liver function abnormality. Patients who have liver function test (LFT)s (specifically, total bilirubin, aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) >= twice the upper limit of normal should be evaluated by a gastrointestinal (GI) physician unless there is a clear precipitating factor (such as an azole, MTX, trimethoprim-sulfamethoxazole, or another drug). If the GI physician considers that HCT on the protocol is contraindicated, that patient will be excluded from the protocol. Patients with Gilbert's syndrome and no other known liver function abnormality or with reversible drug-related transaminitis do not necessarily require GI consultation and may be included on the protocol.
  • Patients who have received previous myeloablative allogeneic or autologous transplantation.
  • Patients with a life expectancy < 12 months from co-existing disease other than the leukemia.
  • Patients who are pregnant or breast-feeding.
  • Patients of childbearing age who are presumed to be fertile and are unwilling to use an effective birth control method or refrain from sexual intercourse during and for 12 months post-HCT.
  • Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI.
  • Patients with a known hypersensitivity to tacrolimus, MTX or thymoglobulin
  • Patients who have received checkpoint inhibitors within three months of transplantation unless an exception is made by the PI
  • DONOR: Donors who are HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection. Test must be performed using Food and Drug Administration (FDA) licensed, cleared, and approved test kits (serological and/or nucleic acid amplification test [NAT] and/or other approved testing) in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory.
  • DONOR: Unrelated donors donating outside of the United States of America (USA).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marie Bleakley 206-667-6572 mbleakle@fredhutch.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03970096
Other Study ID Numbers  ICMJE RG1005364
9749 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
NCI-2019-03188 ( Registry Identifier: CTRP )
P30CA015704 ( U.S. NIH Grant/Contract )
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
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Marie Bleakley Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date April 2021

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

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