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

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

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.

Study Overview

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

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.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marie Bleakley; Phone Number: 206-667-6572; Email: mbleakle@fredhutch.org

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital of Los Angeles
      • Contact: Ashley Gray; Phone Number: 323-361-3530; Email: agray@chla.usc.edu
      • Principal Investigator: Ashley Gray
  • District of Columbia
    • Washington, District of Columbia, United States, 200100
      • Withdrawn
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Not yet recruiting
      • Children's Healthcare of Atlanta
      • Contact: Benjamin Watkins; Phone Number: 404-785-1272; Email: Benjamin.watkins@choa.org
      • Principal Investigator: Benjamin Watkins
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa/Holden Comprehensive Cancer Center
      • Principal Investigator: Rajat Sharma
      • Contact: Rajat Sharma; Phone Number: 319-356-2405; Email: rajat-sharma@uiowa.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Not yet recruiting
      • Dana Farber / Boston Children's Hospital
      • Contact: Susanne Baumeister; Phone Number: 617-632-4687; Email: susanne_baumeister@dfci.harvard.edu
      • Principal Investigator: Susanne Baumeister
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Foundation
      • Contact: Rabi Hanna; Phone Number: 216-444-0663; Email: HANNAR2@ccf.org
      • Principal Investigator: Rabi Hanna
    • Cleveland, Ohio, United States, 44106
      • Not yet recruiting
      • UH Rainbow Babies and Children's Hospital (University Hospitals Cleveland Medical Center)
      • Principal Investigator: Mari Dallas
      • Contact: Mari Dallas; Phone Number: 216-844-3345; Email: mari.dallas@uhhospitals.org
  • Oregon
    • Portland, Oregon, United States, 97239
      • Not yet recruiting
      • Oregon Health and Science University
      • Contact: Eneida Nemecek; Phone Number: 503-494-5675; Email: nemeceke@ohsu.edu
      • Principal Investigator: Eneida Nemecek
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
      • Contact: Jessie Barnum; Email: jessie.barnum@chp.edu
      • Principal Investigator: Jessie Barnum
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Principal Investigator: Marie Bleakley
      • Contact: Marie Bleakley; Phone Number: 206-667-7746; Email: mbleakle@fredhutch.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 22 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

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.
• Age 6 months to 22 years at the time informed consent.
• 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 >=14 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 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 principal investigator (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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Drug: Cyclophosphamide; Given IV; Other Names: Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; Cycloblastin; Cytophosphane; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 2-Fluorovidarabine; 2-Fluoro-9-beta-arabinofuranosyladenine; Drug: Methotrexate; Given IV; Other Names: Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; Emtexate; Emthexat; Emthexate; Farmitrexat; Medsatrexate; Methoblastin; Rheumatrex; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Bussulfam; Busulfanum; Busulphan; Misulban; Myeleukon; Drug: Tacrolimus; Given IV; Other Names: Prograf; Hecoria; Fujimycin; Protopic; Drug: Thiotepa; Given IV; Other Names: Tepadina; Oncotiotepa; STEPA; Tespamin; Tespamine; Thio-Tepa; Thiofosfamide; Thiofozil; Thiophosphamide; Thiophosphoramide; 1,1',1"-phosphinothioylidynetrisaziridine; triethylenethiophosphoramide; 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.	Drug: Cyclophosphamide; Given IV; Other Names: Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; Cycloblastin; Cytophosphane; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 2-Fluorovidarabine; 2-Fluoro-9-beta-arabinofuranosyladenine; Drug: Methotrexate; Given IV; Other Names: Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; Emtexate; Emthexat; Emthexate; Farmitrexat; Medsatrexate; Methoblastin; Rheumatrex; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Bussulfam; Busulfanum; Busulphan; Misulban; Myeleukon; Drug: Tacrolimus; Given IV; Other Names: Prograf; Hecoria; Fujimycin; Protopic; Drug: Thiotepa; Given IV; Other Names: Tepadina; Oncotiotepa; STEPA; Tespamin; Tespamine; Thio-Tepa; Thiofosfamide; Thiofozil; Thiophosphamide; Thiophosphoramide; 1,1',1"-phosphinothioylidynetrisaziridine; triethylenethiophosphoramide; Procedure: Allogeneic Bone Marrow Transplantation; Receive unmanipulated T cell replete BM; Other Names: Allo BMT; Allogeneic BMT; Allogeneic Blood and Marrow Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility achievement	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)	Up to 2 years
Engraftment of neutrophils by day 28 (Feasibility)	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.	At day 28
Current-graft versus host disease (GVHD)-free, relapse-free survival (Randomized Controlled Trial [RCT])	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.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronic GVHD (cGVHD) meeting National Institutes of Health (NIH) criteria and requiring prednisone (RCT)	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.	At 1 and 2 years
Proportion of subjects alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD (RCT)	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.	At 3, 6, 9, 12, 15, 18, 21 and 24 months post HCT

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Marie Bleakley, Fred Hutch/University of Washington Cancer Consortium

Publications and helpful links

General Publications

• Bleakley M. Naive T-cell depletion in stem cell transplantation. Blood Adv. 2020 Oct 13;4(19):4980. doi: 10.1182/bloodadvances.2020001888.

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2019
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: December 17, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lung Diseases; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Bronchial Diseases; Anemia; Lung Diseases, Obstructive; Precancerous Conditions; Leukemia, Lymphoid; Bronchitis; Anemia, Refractory; Bronchiolitis Obliterans; Bronchiolitis; Organizing Pneumonia; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease; Graft vs Host Disease; Anemia, Refractory, with Excess of Blasts; Leukemia, Biphenotypic, Acute; Bronchiolitis Obliterans Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Thiotepa; Busulfan; Vidarabine
• Other Study ID Numbers: RG1003345 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); 9880 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2018-01752 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P01CA018029-43 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No