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Donor Stem Cell Transplantation Using α/β+ T-lymphocyte Depleted Grafts From HLA Mismatched Donors

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ClinicalTrials.gov Identifier: NCT03615105
Recruitment Status : Recruiting
First Posted : August 3, 2018
Last Update Posted : July 10, 2020
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
This study is being done to learn whether a new method to prevent rejection between the donor immune system and the patient's body is effective.

Condition or disease Intervention/treatment Phase
Acute Lymphoid Leukemia (ALL) Acute Myeloid Leukemia (AML) Chronic Myeloid Leukemia (CML) Hodgkin Lymphoma Non-Hodgkin Lymphoma Chronic Lymphocytic Leukemia Radiation: Hyperfractionated total body irradiation Drug: Thiotepa Drug: Cyclophosphamide Drug: Busulfan Drug: Fludarabine Drug: Melphalan Drug: Clofarabine Procedure: HPC(A) stem cell allograft Drug: Rituximab Device: Rabbit antithymocyte globulin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will receive one of three myeloablative conditioning regimens followed by a Alpha/beta+ T-cell depleted peripheral blood stem cell product and short course tacrolimus. Donors are HLA mismatched unrelated adults or haploidentical family members.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Cell Transplantation Using α/β+ T-lymphocyte Depleted Grafts From HLA Mismatched Donors
Actual Study Start Date : July 25, 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021


Arm Intervention/treatment
Experimental: Radiation, Thiotepa & Cyclophosphamide Radiation: Hyperfractionated total body irradiation
Hyperfractionated TBI is administered by a linear accelerator at a dose rate of <20 cGy/minute. Doses of 125 cGy/fraction are administered at a minimum interval of 4 hours between fractions, three times/day for a total of 11 or 12 doses (1,375 or 1,500 cGy) over 4 days (days -9 through -6).

Drug: Thiotepa
Thiotepa 5 mg/kg IV

Drug: Cyclophosphamide
Cyclophosphamide 60 mg/kg IV

Procedure: HPC(A) stem cell allograft
All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.

Drug: Rituximab
Rituximab 200 mg IV flat dose

Device: Rabbit antithymocyte globulin
Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion.

Experimental: Busulfan, Fludarabine & Melphalan Drug: Busulfan
Busulfan (adult/ped dose)

Drug: Fludarabine
Fludarabine 25 mg/m2 IV

Drug: Melphalan
Melphalan 70 mg/m2 IV

Procedure: HPC(A) stem cell allograft
All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.

Drug: Rituximab
Rituximab 200 mg IV flat dose

Device: Rabbit antithymocyte globulin
Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion.

Experimental: Clofarabine, Thiotepa & Melphalan Drug: Thiotepa
Thiotepa 5 mg/kg IV

Drug: Melphalan
Melphalan 70 mg/m2 IV

Drug: Clofarabine
Clofarabine 20-30 mg/m2 IV

Procedure: HPC(A) stem cell allograft
All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system.

Drug: Rituximab
Rituximab 200 mg IV flat dose

Device: Rabbit antithymocyte globulin
Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion.




Primary Outcome Measures :
  1. the number of incidences of grade 3-4 acute GVHD [ Time Frame: 2 years ]
    The intervention will be considered unpromising if the rate of GVHD is greater than 40% and promising if the rate is 20% or less.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Subject Inclusion Criteria:

  • Patients with any of the following hematologic malignancies who are considered to be eligible for allogeneic transplantation:

    • Acute lymphoid leukemia (ALL) in first complete remission (CR1) with high risk for relapse including:

      • Detectable minimal residual disease by either multicolor flow cytometry or by genomic assay after initial induction therapy
      • t(9;22) or detected BCR-ABL1 translocation by genomic methodologies
      • BCR-ABL1-Like B-ALL [23] including mutations of IKZF1 or CRLF2
      • Translocations or mutations involving 11q23 (MLL) gene.
      • Hypodiploid karyotype
      • Deletion of 9p
      • Loss of 17p or TP53 mutation
      • T-lymphocyte lineage antigen expression (T-ALL)
      • Prior CNS or other extramedullary involvement
      • WBC count ≥ 100,000 cells/μL at diagnosis
      • Acute biphenotypic or bilineal leukemia in CR1
    • Acute myeloid leukemia (AML) in CR1 with

      • Detectable minimal residual disease (MRD) by either multicolor flow cytometry or by genomic assay after initial induction therapy
      • In the absence of MRD any intermediate or high risk features according to the European LeukemiaNet 2017 guidelines indlucing:
  • Mutated FL T3-ITD or FL T3-TKD
  • Cytogenetic abnormalities not classified as favorable
  • Cytogenetic abnormalities associated with myelodysplastic syndrome including abnormalities of chromosome 5, 7, or 17p
  • Complex karyotype or monosomal karyotype
  • t(9;11)(p21.1;q23.3); MLL-KMT2A or other rearrangements of KMT2A
  • t(9;11); BCR-ABL1
  • Inversions or translocations of chromosome 3
  • T(6;9)(p23;q34.1); DEK-NUP214
  • Somatic mutation of RUNX1, ASX1 or TP53

    • Extramedullary involvement
    • WBC count ≥100,000 cells/μL at diagnosis

      • Relapsed acute leukemia with ≤ 5% blasts in the bone marrow prior to transplantation (i.e. CR2 or greater).
      • Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN overlap syndrome with ≤ 10% blasts and at least one of the following:
    • Revised International Prognostic Scoring System risk score of INT, HIGH, or VERY HIGH at the time of transplant evaluation.
    • Life-threatening cytopenias
    • Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype.
    • Therapy related disease or disease evolving from other malignant processes.

      • Chronic myelomonocytic leukemia (CMML) with ≤ 10% blasts prior to transplantation.
      • Chronic myeloid leukemia (CML) meeting one of the following criteria:
    • Failed or are intolerant to BCR-ABL tyrosine kinase inhibitors.
    • CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g. T351I mutation).
    • CML with accelerated or blast phase with <10% blasts after therapy.

      • Chronic lymphocytic leukemia (CLL) with high risk disease as defined by the EBMT consensus criteria
      • Hodgkin lymphoma meeting both of the following criteria:
    • Responding to therapy prior to enrollment
    • Relapse after autologous bone marrow transplant or are ineligible for autologous bone marrow transplant.

      °Non-Hodgkin lymphoma meeting both of the following criteria:

    • Responding to therapy prior to enrollment.
    • Relapse after prior autologous bone marrow transplant or are ineligible for autologous bone marrow transplant.
    • Patients aged from birth through 65 years old are eligible.
    • Patients must have Karnofsky/Lanksy performance status ≥70%.
    • Cardiac left ventricular ejection fraction ≥50% at rest.
    • Serum bilirubin ≤ 2 mg/dL. Patients with Gilbert's disease or ongoing hemolytic anemia are acceptable if the direct bilirubin is ≤ 2 mg/dL.
    • AST and ALT ≤ 2.5 x ULN unless thought to be disease related
    • Estimated or measured creatinine clearance > 50 mL/min/1.73 m^2 body surface area.
    • Adult patients and pediatric patients capable of performing pulmonary function studies must have hemoglobin adjusted pulmonary DLCO ≥50% of predicted.

Subject Exclusion Criteria:

  • Persons with a HLA matched sibling donor or a 8/8 allele level HLA-matched unrelated donor.
  • Female patients who are pregnant or breast-feeding.
  • Persons with an infection that is not responding to antimicrobial therapy.
  • Persons who are seropositive for HIV.
  • Persons with active/detectable central nervous system malignancy.
  • Persons who do not meet the age and organ function criteria specified above.
  • Presence of psychiatric or neurologic disease, or lack of social support that limits the patient's ability to comply with the treatment protocol including supportive care, followup, and research tests.
  • Prior allogeneic hematopoietic cell transplantation are ineligible.
  • Patients with history of other malignancy within 5 years of study therapy are ineligible with the following exceptions: Low grade prostate cancer (Gleason's ≤6) treated with curative intent, breast ductal carcinoma in situ treated with curative intent, or nonmelanomatous skin carcinomas.

Donor Inclusion and Exclusion Criteria:

  • Partially HLA-matched unrelated volunteers (allele level matched at 6-7 of 8 HLA loci: -A, -B, -C, and -DRB1) are eligible.
  • Related, haploidentical donors are eligible.
  • Able to provide informed consent to the donation process
  • Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines.

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): NCT03615105


Contacts
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Contact: Brian Shaffer, MD 212-639-2212 shaffeb1@mskcc.org
Contact: Miguel-Angel Perales, MD 212-639-8682

Locations
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United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Brian Shaffer, MD    212-639-2212      
Contact: Miguel-Angel Perales, MD    212-639-8682      
Principal Investigator: Brian Shaffer, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Investigators
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Principal Investigator: Brian Shaffer, MD Memorial Sloan Kettering Cancer Center
Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03615105    
Other Study ID Numbers: 18-224
First Posted: August 3, 2018    Key Record Dates
Last Update Posted: July 10, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Memorial Sloan Kettering Cancer Center:
Allogeneic Hematopoietic Cell Transplantation
α/β+ T-lymphocyte
18-224
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cyclophosphamide
Melphalan
Busulfan
Thiotepa
Rituximab
Fludarabine
Clofarabine
Antilymphocyte Serum
Thymoglobulin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs