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Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation

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ClinicalTrials.gov Identifier: NCT03663933
Recruitment Status : Recruiting
First Posted : September 10, 2018
Last Update Posted : September 26, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Blood stem cells in the bone marrow make all the cells to normally defend a body against disease. Allogeneic blood or marrow transplant is when these stem cells are transferred from one person to another. Researchers think this treatment can provide a new, healthy immune system to correct T-cell problems in some people.

Objective:

To see if allogeneic blood or bone marrow transplant is safe and effective in treating people with T-cell problems.

Eligibility:

Donors: Healthy people ages 4 and older

Recipients: People the same age with abnormal T-cell function causing health problems

Design:

All participants will be screened with:

  • Medical history
  • Physical exam
  • Blood, heart, and urine tests

Donors will also have an electrocardiogram and chest x-ray. They may have veins tested or a pre-anesthesia test.

Recipients will also have lung tests.

Some participants will have scans and/or bone marrow collected by needle in the hip bones.

Donors will learn about medicines and activities to avoid and repeat some screening tests.

Some donors will stay in the hospital overnight and have bone marrow collected with anesthesia.

Other donors will get shots for several days to stimulate cells. They will have blood removed by plastic tube (IV) in an arm vein. A machine will remove stem cells and return the rest of the blood to the other arm.

Recipients will have:

  • More bone marrow and a small fragment of bone removed
  • Dental, diet, and social worker consultations
  • Scans
  • Chemotherapy and antibody therapy for 2 weeks
  • Catheter inserted in a chest or neck vein to receive donor stem cells
  • A hospital stay for several weeks with more medicines and procedures
  • Multiple follow-up visits...

Condition or disease Intervention/treatment Phase
Lymphoproliferative Disorders Autoimmune Lymphoproliferative Primary T-cell Immunodeficiency Disorders Immune System Diseases Common Variable Immunodeficiency Drug: Immunosuppression Only Conditioning (IOC) Drug: Reduced Intensity Conditioning (RIC) Drug: GVHD Prophylaxis Procedure: Allogeneic HSC Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 177 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
Actual Study Start Date : September 4, 2018
Estimated Primary Completion Date : May 27, 2023
Estimated Study Completion Date : May 1, 2024


Arm Intervention/treatment
Experimental: 1/RIC Arm
Reduced Intensity Conditioning Arm
Drug: Reduced Intensity Conditioning (RIC)
E-ATG 40 mg/kg IV once daily for days -14 and -13. Prednisone: Tapering doses, given orally daily, and given prior to each daily dose of e-ATG on days -14 and -13 Pentostatin:4 mg/m2 /day IV on days -11 and -7, cyclophosphamide:3 mg/kg orally daily on days -11 through -4 Busulfan IV, pharmokinetically dosed, on days -3 and -2.

Drug: GVHD Prophylaxis
High-dose, post- transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, Mesna: 25-50 mg/kg weight based dosing, Tacrolimus 0.02 mg /kg on days +5 through +90, and mycophenolate mofetil (MMF) 15 mg /kg on days +5 through +25

Procedure: Allogeneic HSC
Stem cell transplant

Experimental: 2/IOC Arm
Immunosuppression Only Conditioning Arm
Drug: Immunosuppression Only Conditioning (IOC)
E-ATG 40 mg/kg IV once daily for days -14 and -13. Prednisone: Tapering doses, given orally daily, and given prior to each daily dose of e-ATG on days -14 and -13 Pentostatin:4 mg/m2 /day IV on days -9 and -5, cyclophosphamide:5 mg/kg orally daily on days -9 through -2

Drug: GVHD Prophylaxis
High-dose, post- transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, Mesna: 25-50 mg/kg weight based dosing, Tacrolimus 0.02 mg /kg on days +5 through +90, and mycophenolate mofetil (MMF) 15 mg /kg on days +5 through +25

Procedure: Allogeneic HSC
Stem cell transplant

No Intervention: 3/Donor Arm
Healthy Donors; Donors for recipients in Arm 1 or Arm 2



Primary Outcome Measures :
  1. To estimate the percentage of recipients with >50% donor T cell chimerism and graft-failure free survival [ Time Frame: Day +180 post-HCT ]
    proportion with > 50% donor T cell chimerism and without death or graft failure


Secondary Outcome Measures :
  1. Event-free survival [ Time Frame: 1 , 3 and 5 years post transplant ]
    Time from transplant to death of any cause or other event, including disease relapse, graft failure, grade 3-4 acute GVHD, chronic GVHD requiring systemic therapy, or receipt of post-transplant donor cell infusion.

  2. Transplant-related mortality [ Time Frame: +180 and 1 year post ]
    Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant.

  3. Incidence of Chronic Graft versus-host disease [ Time Frame: 1 and 2 years post transplant ]
    Cumulative incidence of chronic graft versus host disease at 1 and 2 years post transplant.

  4. Incidence of Acute Graft versus-host disease [ Time Frame: 1 year post transplant ]
    Cumulative incidence of acute graft versus host disease at 1 year post transplant

  5. Overall survival [ Time Frame: 1 , 3 and 5 years post transplant ]
    Time from transplant to death of any cause.

  6. Kinetics and durability of engraftmenrt [ Time Frame: days +21, +28, +35, +42 and +60 after allo BMT ]
    The percentage of donor T-, B-, NK-, and myeloid cell populations at days +28, +42, +60, +100, +180, and 1 year post transplant.

  7. Kinetics and durability of lineage-specific donor chimerism [ Time Frame: +28, +42, +60, +100, +180, and 1 year after HCT ]
    Median amount of patients who have early chimerism

  8. Secondary graft failure [ Time Frame: 1 , 3 and 5 years post-transplant ]
    Cumulative incidence of secondary graft failure at 1 year post transplant.

  9. Disease free survival [ Time Frame: 1 , 3 and 5 years post-transplant ]
    Time from transplant to death of any cause or disease relapse.



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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA - RECIPIENT:
  • Age greater than or equal to 4 years
  • TCP/D deemed to be of sufficient past severity to warrant HCT that meets at least one of the criteria below:

    -- Identified germline T-cell activating mutation in the PI3k pathway

    --Identified ADA2 deficiency (biallelic mutations in CECR1 (ADA2) and/or phenotypically with low ADA2 level) leading to neutropenia requiring chronic GCSF therapy or to transfusion-dependent anemia or thrombocytopenia

    --T-cell infiltration of liver, spleen, lymph nodes, marrow, lungs, gut, or other organs by T cells, as evidenced by laboratory, radiographic, and/or anatomic pathology evaluation, resulting in organ dysfunction and/or organomegaly

    -- Latent herpesvirus infection in T lymphocytes

    -- History of or active evidence of hemophagocytic lymphohistiocytosis (HLH)

    -- Recurrent or prolonged fevers attributed to immune dysregulation

    -- T-cell population in blood and/or marrow with immunophenotype of large granular lymphocytes (LGL), with or without clonality or lymphocytosis

    • T-cell lymphoproliferative disorder in the setting of an underlying immune defect
    • Immune-mediated cytopenias of one lineage requiring transfusion or GCSF support or of 2 or 3 lineages with or without transfusion or support
    • Chronic active EBV
  • At least one potential 7-8/8 HLA-matched related (excluding an identical twin) or unrelated donor (at HLA-A, -B, -C, and -DR), or an HLA-haploidentical related donor, based on initial low resolution unrelated donor search and/or at least one biologically- related family member who has at least a 25% chance of being at minimum an HLA- haploidentical match and is potentially suitable to donate based on reported family history. HLA typing of potential donors and/or mutation testing does not need to be completed for eligibility.
  • Adequate end-organ function, as measured by:

    • Left ventricular ejection fraction (LVEF) greater than or equal to 40% by 2D echocardiogram ECHO, or left ventricular shortening fraction greater than or equal to 20% by ECHO for subjects receiving RIC, or LVEF greater than or equal to 30% if the subject has radiologic evidence of aortic, renal, or coronary artery vasculitis. LVEF greater than or equal to 30% for subjects receiving IOC.
    • Pulmonary function tests: DLco (corrected for hemoglobin) and FEV1 greater than or equal to 40% of predicted for the RIC arm, and greater than or equal to 30% predicted for the IOC arm; or in pediatric subjects, if unable to perform pulmonary function tests, there should be no evidence of dyspnea at rest, no requirement for supplemental oxygen, and oxygen saturation >92% on room air. Calculations will be based on the USA- ITS-NIH reference.
    • Bilirubin greater than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or hemolysis) for subjects receiving RIC and bilirubin greater than or equal to 5.0 mg/dL for subjects receiving IOC (unless due to Gilbert s syndrome or hemolysis); ALT and AST greater than or equal to 5 x ULN for subjects receiving RIC or greater than or equal to 10 x ULN for subjects receiving IOC. Subjects who are above these bilirubin, ALT, or AST thresholds may be eligible for the RIC or IOC arm if evaluated by a hepatologist who deems the liver function test abnormalities to be potentially reversible with HCT.
    • Estimated creatinine clearance of greater than or equal to 50 mL/min/1.73 m^2, calculated using eGRF in the clinical lab for adults and the Schwartz formula for pediatric subjects, if eGFR not reported by the clinical lab.
  • Adequate central venous access potential
  • Karnofsky (adults) or Lansky (children) performance status of greater than or equal to 50% or ECOG performance status of 2 or less for the RIC arm and greater than or equal to 30% or ECOG performance status of 3 or less for the IOC arm
  • Ability of subject or parent/legal guardian to understand and the willingness to sign a written informed consent document
  • Not pregnant or breastfeeding. As therapeutic agents used in this trial may be harmful to a fetus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-allo HCT. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately.
  • Disease status: Subjects with lymphoproliferative disorder (LPD), LGL, HLH, or other TCP/D disorders requiring standard therapies to prepare for HCT should be referred in remission if possible. However, these diseases are often aggressive and require swift evaluation for HCT while concurrently attempting to establish disease control through the administration of standard therapies. If ongoing therapy for the underlying disease outside of the NIH is not in the best interest of the subject according to the clinical judgment of the PI, then the subject may receive standard treatment for his/her underlying TCP/D disorder as a bridge to HCT on this protocol, prior to starting the research phase of the study. If it becomes apparent that the subject will not be able to proceed to HCT, then he/she must come off study. Subjects receiving standard therapy will be told about the therapy, associated risks, potential benefits, alternatives to the proposed therapy, and the availability of receiving the same treatment elsewhere, outside of a research protocol.

EXCLUSION CRITERIA - RECIPIENT:

  • Subjects who are receiving any other investigational agents, with the exception of virus- specific cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HCT.
  • History of allergic reactions to horses or attributed to compounds of similar chemical or biologic composition to agents (e-ATG, steroids, cyclophosphamide, busulfan, pentostatin, tacrolimus, MMF, G-CSF) used in the study
  • Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol or which does not allow for appropriate informed consent
  • HIV positive or other acquired immunodeficiency that, as determined by the PI, interferes with the assessment of TCP/D severity and/or the attribution of clinical manifestations of immunodeficiency to a disorder of TCP/D.
  • MagT1 mutation and active need to take anti-platelet agents and/or therapeutic anti- coagulation that cannot be interrupted during aplasia

INCLUSION CRITERIA - RELATED DONOR:

  • Age greater than or equal to 4 and weight of greater than or equal to 15 kg
  • Karnofsky performance status of 90-100% (adults) or Lansky Play Performance Status of 100% (children)
  • Related donors with at least a haplotype at HLA-A, B, C, and DR loci that is shared with the recipient by high resolution typing, excluding an identical twin, or unrelated donors matched 7-8/8 at HLA-A, B, C, and DR loci by high resolution typing
  • Ability of subject or Legally Authorized Representative to understand and the willingness to sign a written informed consent document; medically fit and willing to donate
  • Related donors: No history of opportunistic infections, autoimmunity, hemoglobinopathy, red cell enzymopathy, or malignancy, apart from non- melanomatous skin cancer or healed cervical cancer in situ.
  • HIV negative, hepatitis B virus surface antigen negative, and hepatitis C virus antibody negative.
  • Related donors undergoing bone marrow harvest should be deemed fit for the operative procedure and related donors undergoing apheresis should be deemed fit for the collection procedure.
  • Related donors for recipients who have germline monogenetic mutations as the cause of their TCP/D disorder must be unaffected. For recipients with de novo mutations, testing of related donors is largely not required, but is recommended in all cases and is required when the donor is the child of the recipient. Mutation testing should be performed by a CLIA-certified lab, if such testing is available. For donors who carry one wild type allele and one mutated allele of the disorder of TCP/D which is inherited in either an autosomal recessive or X-linked fashion, the donor must have no discernable symptomatology or penetrance of the mutation suggesting that they are affected carriers. This may need to be verified through disease-appropriate quantitative and functional assays to assess the function of the potential donor s immune system.

Furthermore, the X-chromosome inactivation pattern may need to be assessed for female carriers of X-linked diseases if the disease is not one where complete favorable lyonization is not universal and if they are considered as potential donors, to confirm favorable and complete lyonization of hematopoietic cells. For disorders of TCP/D inherited in an autosomal dominant fashion, donors who have one mutated allele for the recipient s disease will be considered ineligible to donate, regardless of the donor s phenotype. Additional blood tests may be required to assess for quantitative and/or qualitative defects in the donor s immune system, particularly in cases where mutation testing is not available or the mutation underlying the disorder of TCP/D is not identified.

  • Related donors will undergo the Donor Health History Screen by skilled staff in the Blood Services Section for adult donors and age-appropriate questioning when indicated for pediatric donors to determine donor eligibility using standard DTM criteria.

INCLUSION CRITERIA RELATED DONOR

- Related donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood, urine, and marrow specimens for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but is not required for clinical donation, so it is possible that not all related donors will enroll onto this study.

EXCLUSION CRITERIA - RELATED DONOR:

-None

INCLUSION CRITERIA (UNRELATED DONOR):

-Unrelated donors will be evaluated in accordance with existing NMDP Standard Policies and Procedures, available at: http://bethematch.org/About-Us/Global- transplant-network/Standards/, except for the additional requirement of EBV serostatus testing for clinical purposes of donor selection. Note that participation in this study is offered to all unrelated donors but not required for clinical donation, so it is possible that not all unrelated donors will enroll on this study. Unrelated donors only enroll if they contribute research specimens, which is optional.

EXCLUSION CRITERIA (UNRELATED DONOR):

-Unrelated donors: failure to qualify as a National Marrow Donor Program (NMDP) donor per current NMDP Standards, available at: http://bethematch.org/About-Us/Global-transplant-network/Standards/. Exceptions to donor eligibility (e.g. foreign travel, tattoos) do not automatically exclude the donor and will be reviewed by the PI.


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): NCT03663933


Contacts
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Contact: Jennifer L Sadler (240) 760-6172 jennifer.sadler@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
United States, Minnesota
National Marrow Donor Program Recruiting
Minneapolis, Minnesota, United States, 55401
Contact: John Miller, Ph.D.    612-627-5800      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jennifer A Kanakry, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03663933     History of Changes
Other Study ID Numbers: 180135
18-C-0135
First Posted: September 10, 2018    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 20, 2019

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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 National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Haploidentical
Autoimmunity
Immune Dysregulation
Congenital
Opportunistic Infection
Additional relevant MeSH terms:
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Lymphoproliferative Disorders
Immunologic Deficiency Syndromes
Common Variable Immunodeficiency
Disease
Immune System Diseases
Pathologic Processes
Lymphatic Diseases
Immunoproliferative Disorders