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

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

Study Description

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

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Brian Shaffer, MD; 212-639-2212; shaffeb1@mskcc.org

Contact: Miguel-Angel Perales, MD; 212-639-8682

Locations

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

• Principal Investigator: Brian Shaffer, MD; Memorial Sloan Kettering Cancer Center

More Information

Additional Information:

Memorial Sloan Kettering Cancer Center 

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT03615105
• Other Study ID Numbers: 18-224
• First Posted: August 3, 2018
• Last Update Posted: July 10, 2020
• Last Verified: July 2020

• 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:

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