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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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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/Acute Myeloid Leukemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (chemotherapy, naive T-cell depleted PBSC)<br>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<br>* Undergo TBI<br>* Other names: Whole Body Irradiation;Drug: Thiotepa<br>* Given IV<br>* Other names: triethylenethiophosphoramide;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cytophosphane;Drug: Busulfan<br>* Given IV<br>* Other names: Myeleukon;Drug: Tacrolimus<br>* Given IV<br>* Other names: Protopic;Drug: Methotrexate<br>* Given IV<br>* Other names: Rheumatrex;Procedure: Naive T Cell-Depleted Hematopoietic Stem Cell Transplantation<br>* Receive naive T-cell depleted PBSCs<br>|
| Active Comparator: Arm II (chemotherapy, unmanipulated T cell replete BM)<br>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<br>* Undergo TBI<br>* Other names: Whole Body Irradiation;Drug: Thiotepa<br>* Given IV<br>* Other names: triethylenethiophosphoramide;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cytophosphane;Drug: Busulfan<br>* Given IV<br>* Other names: Myeleukon;Procedure: Allogeneic Bone Marrow Transplantation<br>* Receive unmanipulated T cell replete BM<br>* Other names: Allogeneic BMT;Drug: Tacrolimus<br>* Given IV<br>* Other names: Protopic;Drug: Methotrexate<br>* Given IV<br>* Other names: Rheumatrex;|

What is the study measuring?
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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 |