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Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults With Blood Cancers Undergoing Donor Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT03779854
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : August 25, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase II trial studies how well naive T-cell depletion works in preventing chronic graft-versus-host disease in children and young adults with blood cancers undergoing donor stem cell transplant. Sometimes the transplanted white blood cells from a donor attack the body's normal tissues (called graft versus host disease). Removing a particular type of T cell (naive T cells) from the donor cells before the transplant may stop this from happening.

Condition or disease Intervention/treatment Phase
Acute Biphenotypic Leukemia Acute Leukemia Acute Leukemia of Ambiguous Lineage Acute Lymphoblastic Leukemia Acute Undifferentiated Leukemia Allogeneic Hematopoietic Stem Cell Transplantation Recipient Blastic Plasmacytoid Dendritic Cell Neoplasm Blasts Under 25 Percent of Bone Marrow Nucleated Cells Blasts Under 5 Percent of Bone Marrow Nucleated Cells Mixed Phenotype Acute Leukemia Myelodysplastic Syndrome With Excess Blasts-1 Myelodysplastic Syndrome With Excess Blasts-2 Radiation: Total-Body Irradiation Drug: Thiotepa Drug: Fludarabine Drug: Cyclophosphamide Drug: Busulfan Procedure: Allogeneic Bone Marrow Transplantation Drug: Tacrolimus Drug: Methotrexate Procedure: Naive T Cell-Depleted Hematopoietic Stem Cell Transplantation Phase 2

Detailed Description:

Patients are randomized to 1 of 2 arms. All patients receive 1 of 3 conditioning regimens.

CONDITIONING REGIMEN A: Patients undergo total body irradiation (TBI) twice daily (BID) on days -10 to -7, then receive thiotepa intravenously (IV) over 3 hours once daily (QD) on days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2.

CONDITIONING REGIMEN B: Patients undergo TBI BID on days -8 to -5, then receive fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on days -3 and -2.

CONDITIONING REGIMEN C: Patients receive fludarabine IV over 30 minutes QD on days -6 to -2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID on day -1.

ARM I: Patients receive naive T-cell depleted PBSCs on day 0.

ARM II: Patients receive unmanipulated T cell-replete BM on day 0.

GVHD PROPHYLAXIS: All patients receive tacrolimus IV on days -1 to +50 followed by a taper in the absence of grade II-IV aGVHD. Patients also receive methotrexate IV on days +1, +3, +6, and +11.

After completion of study treatment, patients are followed up periodically.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-Center Phase II Randomized Controlled Trial of Naïve T Cell Depletion for Prevention of Chronic Graft-Versus-Host Disease in Children and Young Adults
Actual Study Start Date : August 29, 2019
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: Arm I (chemotherapy, naive T-cell depleted PBSC)

CONDITIONING REGIMEN A: Patients undergo TBI BID on days -10 to -7, then receive thiotepa IV over 3 hours QD on days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2.

CONDITIONING REGIMEN B: Patients undergo TBI BID on days -8 to -5, then receive fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on days -3 and -2.

CONDITIONING REGIMEN C: Patients receive fludarabine IV over 30 minutes QD on days -6 to -2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID on day -1.

TRANSPLANT: Patients receive naive T-cell depleted PBSCs on day 0.

GVHD PROPHYLAXIS: All patients receive tacrolimus IV beginning on day -1 and methotrexate IV on days 1, 3, 6, and 11.

Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation
  • SCT_TBI
  • TBI
  • Whole Body Irradiation

Drug: Thiotepa
Given IV
Other Names:
  • 1,1',1"-phosphinothioylidynetrisaziridine
  • Oncotiotepa
  • STEPA
  • Tepadina
  • Tespamin
  • Tespamine
  • Thio-Tepa
  • Thiofosfamide
  • Thiofozil
  • Thiophosphamide
  • Thiophosphoramide
  • triethylenethiophosphoramide

Drug: Fludarabine
Given IV
Other Names:
  • 2-Fluoro-9-beta-arabinofuranosyladenine
  • 2-Fluorovidarabine
  • Fluradosa

Drug: Cyclophosphamide
Given IV
Other Names:
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • Cycloblastin
  • Cytophosphane

Drug: Busulfan
Given IV
Other Names:
  • Bussulfam
  • Busulfanum
  • Busulfex
  • Busulphan
  • Misulban
  • Misulfan
  • Mitosan
  • Myeleukon

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

Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Medsatrexate
  • Methoblastin
  • Rheumatrex

Procedure: Naive T Cell-Depleted Hematopoietic Stem Cell Transplantation
Receive naive T-cell depleted PBSCs

Active Comparator: Arm II (chemotherapy, unmanipulated T cell replete BM)

CONDITIONING REGIMEN A: Patients undergo TBI BID on days -10 to -7, then receive thiotepa IV over 3 hours QD on days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2.

CONDITIONING REGIMEN B: Patients undergo TBI BID on days -8 to -5, then receive fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on days -3 and -2.

CONDITIONING REGIMEN C: Patients receive fludarabine IV over 30 minutes QD on days -6 to -2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID on day -1.

TRANSPLANT: Patients receive unmanipulated T cell-replete BM on day 0.

GVHD PROPHYLAXIS: All patients receive tacrolimus IV beginning on day -1 and methotrexate IV on days 1, 3, 6, and 11.

Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation
  • SCT_TBI
  • TBI
  • Whole Body Irradiation

Drug: Thiotepa
Given IV
Other Names:
  • 1,1',1"-phosphinothioylidynetrisaziridine
  • Oncotiotepa
  • STEPA
  • Tepadina
  • Tespamin
  • Tespamine
  • Thio-Tepa
  • Thiofosfamide
  • Thiofozil
  • Thiophosphamide
  • Thiophosphoramide
  • triethylenethiophosphoramide

Drug: Fludarabine
Given IV
Other Names:
  • 2-Fluoro-9-beta-arabinofuranosyladenine
  • 2-Fluorovidarabine
  • Fluradosa

Drug: Cyclophosphamide
Given IV
Other Names:
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • Cycloblastin
  • Cytophosphane

Drug: Busulfan
Given IV
Other Names:
  • Bussulfam
  • Busulfanum
  • Busulfex
  • Busulphan
  • Misulban
  • Misulfan
  • Mitosan
  • Myeleukon

Procedure: Allogeneic Bone Marrow Transplantation
Receive unmanipulated T cell replete BM
Other Names:
  • Allo BMT
  • Allogeneic Blood and Marrow Transplantation
  • Allogeneic BMT

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

Drug: Methotrexate
Given IV
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Medsatrexate
  • Methoblastin
  • Rheumatrex




Primary Outcome Measures :
  1. Feasibility achievement [ Time Frame: Up to 2 years ]
    Success defined as achievement of cell selection goals for two consecutive Naive T cells (TN)-depleted peripheral blood stem cells (PBSC) hematopoietic cell transplantation (HCTs) at each study site (Feasibility)

  2. Engraftment of neutrophils by day 28 (Feasibility) [ Time Frame: At day 28 ]
    Success defined as achievement neutrophil engraftment (absolute neutrophil count [ANC] >= 500/mm^3) on first day of three consecutive laboratory values obtained on different days.

  3. Current-graft versus host disease (GVHD)-free, relapse-free survival (Randomized Controlled Trial [RCT]) [ Time Frame: At 1 year ]
    Defined as alive, no relapse after HCT, no current GVHD requiring prednisone, no graft rejection or graft failure. The proportion of subjects meeting the primary endpoint will be described in each arm with 90% confidence intervals (CI) and compared between arms using the chi-square test. A two-sided 10% significance level will be used for this comparison.


Secondary Outcome Measures :
  1. Chronic GVHD (cGVHD) meeting National Institutes of Health (NIH) criteria and requiring prednisone (RCT) [ Time Frame: Up to 2 years ]
    Cumulative incidence curve will be computed for each arm along with a 90% CI at 1 year and 2 years post-HCT. Death and/or relapse prior to occurrence of cGVHD will be considered as competing risks. The cumulative incidence curves will be compared between arms using Gray's test. The maximum severity of cGVHD will also be described in each arm and compared using the chi-squared test.

  2. Proportion of subjects alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD (RCT) [ Time Frame: Up to 24 months post HCT ]
    Proportions of subjects alive without requiring use of prednisone (or equivalent systemic corticosteroid) for GVHD will be estimated with 90% CI for both arms at time points over 24 months, and compared using the chi-squared test.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • The patient must have one of the following diagnoses and be considered to be an appropriate candidate for allogeneic HCT by the study site principal investigator (PI):

    • Acute lymphoblastic leukemia (ALL) with < 5% marrow blasts.
    • Acute myeloid leukemia (AML) with < 25% marrow blasts.
    • Other acute leukemia (OAL) including but not limited to acute biphenotypic leukemia (ABL), ambiguous lineage (ALAL), mixed phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and acute undifferentiated leukemia (AUL) with < 5% marrow blasts.
    • Myelodysplastic syndrome (MDS) with excess blasts (EB-1 and EB-2) and has received cytotoxic induction chemotherapy (excluding small molecule inhibitors and de-methylating agents).
  • Matched related donor (MRD) or matched unrelated donor (MUD) (defined as 8/8 match for human leukocyte antigen [HLA]-A, -B, -C, -DRB1).
  • Planned product type for infusion is PBSC or BM (i.e. not cord blood):

    • For feasibility phase, planned product type for infusion must be PBSC.
    • For RCT, planned product type must be PBSC or BM.
  • Karnofsky or Lansky score >= 60%.
  • Left ventricular ejection fraction (LVEF) at rest >= 40%.
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin) >= 60% predicted by pulmonary function tests (PFTs)

    * Patients who are unable to perform PFTs (age < 6 years or considered developmentally incapable of PFTs): oxygen saturation (by oximetry) must be >= 92% on room air.

  • Total bilirubin =< 2 x upper limit of normal (ULN) (unless value[s] > 2 x ULN are disease- or medication-related).

    * If value(s) are > 2 x ULN and not disease- or medication related, patient must be evaluated by a gastrointestinal (GI) physician. If GI physician considers protocol treatment to be contraindicated for the patient, the patient will not be eligible for the study.

  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2 x ULN (unless value[s] > 2 x ULN are disease- or medication-related).

    * If value(s) are > 2 x ULN and not disease- or medication related, patient must be evaluated by a gastrointestinal GI physician. If GI physician considers protocol treatment to be contraindicated for the patient, the patient will not be eligible for the study.

  • Serum creatinine (SCr) within normal range for age. If SCr is outside normal range for age, creatinine clearance (CrCl) > 40 mL/min/1.73m^2 must be obtained (measured by 24-hour [hr] urine specimen or nuclear glomerular filtration rate [GFR]).

    • Age (Years): Maximum SCr (mg/dL)
    • =< 5: 0.8
    • 6-10: 1
    • 11-15: 1.2
    • > 15: 1.5
  • Recipient informed consent/assent/legal guardian permission documentation must be obtained.
  • DONOR: May be related (MRD) or unrelated (MUD) to the subject.
  • DONOR: Must be matched to the subject at 8/8 HLA alleles (HLA-A, -B, -C, and -DRB1)
  • DONOR: Be >=18 years of age.
  • DONOR: Must be available to donate in the United States of America (USA) (i.e. excludes international donors).
  • DONOR: Must agree to donate BM or PBSC (i.e. agree to donate whichever product type is requested) (applicable only to the RCT phase of this study).
  • DONOR: MUDs:

    • Must give informed consent according to 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)).

      • Tests must be performed using Food and Drug Administration (FDA) licensed, cleared, and approved test kits in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
  • DONOR: MRDs:

    • Must give informed consent using the Related Donor Informed Consent to Participate in a Research Study form
    • Must be negative for human immunodeficiency virus (HIV)-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2, hepatitis B, hepatitis C (serological and/or nucleic acid testing [NAT] and/or other approved testing)
    • Must meet institutional donor eligibility criteria, or be ineligible with statement that the donor is a first or second degree relative (exception 21 CRF 1271.65(b)(i)).

      • Tests must be performed using FDA licensed, cleared, and approved test kits in a CLIA-certified laboratory.

Exclusion Criteria:

  • Active central nervous system (CNS) disease. A patient may have a history of CNS disease; however, any CNS disease must be cleared by the end of the pre-conditioning evaluation. If CNS disease is identified on the first 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 the prevention of GVHD.
  • Patient body weight:

    • Matched related donor (MRD): > 100 kg are ineligible
    • Matched unrelated donor (MUD): > 75 kg must be discussed with the protocol PI prior to enrollment.
  • HIV-positive.
  • Uncontrolled infections must be evaluated by an infectious disease physician and considered suitable to undergo HCT by the study site PI, infectious disease physician and protocol PI. Upper respiratory tract infection (URI) does not constitute an uncontrolled infection in this context.
  • Life expectancy < 3 months from disease other than acute leukemia or myelodysplastic syndrome (MDS).
  • Significant medical condition that would make recipient unsuitable for HCT.
  • Prior allogeneic or autologous HCT.
  • Females who are pregnant or breastfeeding.
  • Patients of child bearing age who are presumed to be fertile and are unwilling to use an effective birth control method or refrain from sexual intercourse during study treatment and for 12 months following HCT.
  • Known hypersensitivity to tacrolimus, fludarabine, or methotrexate (MTX).

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): NCT03779854


Contacts
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Contact: Marie Bleakley 206-667-6572 mbleakle@fredhutch.org

Locations
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United States, California
Children's Hospital of Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Michael Pulsipher    323-361-8840    mpulsipher@chla.usc.edu   
Principal Investigator: Michael Pulsipher         
United States, District of Columbia
Children's National Medical Center Withdrawn
Washington, District of Columbia, United States, 200100
United States, Georgia
Children's Healthcare of Atlanta Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Benjamin Watkins    404-785-1272    Benjamin.watkins@choa.org   
Principal Investigator: Benjamin Watkins         
United States, Iowa
University of Iowa Stead Family Children's Hospital Recruiting
Iowa City, Iowa, United States, 52242
Contact: Arunkumar Modi    319-467-5147    arunkumar-modi@uiowa.edu   
Principal Investigator: Arunkumar Modi         
United States, Massachusetts
Dana Farber / Boston Children's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Susanne Baumeister    617-632-4687    susanne_baumeister@dfci.harvard.edu   
Principal Investigator: Susanne Baumeister         
United States, Ohio
UH Rainbow Babies and Children's Hospital (University Hospitals Cleveland Medical Center) Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Mari Dallas    216-851-8335      
Principal Investigator: Mari Dallas         
Cleveland Clinic Foundation Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Rabi Hanna    216-444-0663    HANNAR2@ccf.org   
Principal Investigator: Jignesh Dalal         
United States, Oregon
Oregon Health and Science University Not yet recruiting
Portland, Oregon, United States, 97239
Contact: Eneida Nemecek    503-494-5675    nemeceke@ohsu.edu   
Principal Investigator: Eneida Nemecek         
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Jessie Barnum       jessie.barnum@chp.edu   
Principal Investigator: Jessie Barnum         
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Marie Bleakley    206-667-7746    mbleakle@fredhutch.org   
Principal Investigator: Marie Bleakley         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Marie Bleakley Fred Hutch/University of Washington Cancer Consortium
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03779854    
Other Study ID Numbers: RG1003345
9880 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
NCI-2018-01752 ( Registry Identifier: CTRP )
P30CA015704 ( U.S. NIH Grant/Contract )
RG1003345 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P01CA018029-43 ( U.S. NIH Grant/Contract )
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: August 25, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Biphenotypic, Acute
Myelodysplastic Syndromes
Anemia, Refractory, with Excess of Blasts
Graft vs Host Disease
Syndrome
Acute Disease
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Anemia, Refractory
Anemia
Vidarabine
Cyclophosphamide
Busulfan
Thiotepa
Methotrexate
Fludarabine