Seattle, Washington 98109


Purpose:

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. This study is comparing naïve T-cell depletion transplantation to the traditional stem cell transplantation. In these transplants, chemotherapy and total-body radiotherapy ('conditioning') are used to kill residual leukemia cells and the patient's normal blood cells, especially immune cells that could reject the donor cells. Following the chemo/radiotherapy, blood stem cells from the donor are infused. These stem cells will grow and eventually replace the patient's original blood system, including red cells that carry oxygen to our tissues, platelets that stop bleeding from damaged vessels, and multiple types of immune-system white blood cells that fight infections. Mature donor immune cells, especially a type of immune cell called T lymphocytes (or T cells) are transferred along with these blood-forming stem cells. T cells are a major part of the curative power of transplantation because they can attack leukemia cells that have survived the chemo/radiation therapy and also help to fight infections after transplantation. However, donor T cells can also attack a patient's healthy tissues in an often-dangerous condition known as Graft-Versus-Host-Disease (GVHD). Drugs that suppress immune cells are used to decrease the severity of GVHD; however, they are incompletely effective and prolonged immunosuppression used to prevent and treat GVHD significantly increases the risk of serious infections. Removing all donor T cells from the transplant graft can prevent GVHD, but doing so also profoundly delays infection-fighting immune reconstitution and eliminates the possibility that donor immune cells will kill residual leukemia cells. Work in animal models found that depleting a type of T cell, called naïve T cells or T cells that have never responded to an infection, can diminish GVHD while at least in part preserving some of the benefits of donor T cells including resistance to infection and the ability to kill leukemia cells. This clinical trial studies how well the selective removal of naïve T cells works in preventing GVHD after peripheral blood stem cell transplants compared to the subjects that receive unmanipulated bone marrow transplants.


Study summary:

Participants are randomized to 1 of 2 arms. All participants receive 1 of 3 conditioning regimens. CONDITIONING REGIMEN A: Participants undergo total body irradiation (TBI) twice daily (BID) on days -10 to -7, then receive thiotepa intravenously (IV) over 4 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: Participants 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: Participants 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: Participants receive naive T-cell depleted PBSCs on day 0. ARM II: Participants receive unmanipulated T cell-replete BM on day 0. GVHD PROPHYLAXIS: All participants receive tacrolimus IV beginning on day -1 and methotrexate IV on days 1, 3, 6, and 11. After completion of study treatment, participants are followed up periodically.


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. - 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 - (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 - 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 time frame. If CNS disease is identified on the first cerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparative regimen a repeat lumbar puncture (LP) with 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).


NCT ID:

NCT03779854


Primary Contact:

Principal Investigator
Marie Bleakley
Fred Hutch/University of Washington Cancer Consortium

Marie Bleakley
Phone: 206-667-7746
Email: mbleakle@fredhutch.org


Backup Contact:

N/A


Location Contact:

Seattle, Washington 98109
United States

Marie Bleakley
Phone: 206-667-7746
Email: mbleakle@fredhutch.org

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: October 09, 2019

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