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Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies

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ClinicalTrials.gov Identifier: NCT02579967
Recruitment Status : Recruiting
First Posted : October 20, 2015
Last Update Posted : August 21, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Allogeneic blood or marrow transplant is when stem cells are taken from one person s blood or bone marrow and given to another person. Researchers think this may help people with immune system problems.

Objective:

To see if allogeneic blood or bone marrow transplant is safe and effective in treating people with primary immunodeficiencies.

Eligibility:

Donors: Healthy people ages 4 or older

Recipients: People ages 4-75 with a primary immunodeficiency that may be treated with allogeneic blood or marrow transplant

Design:

Participants will be screened with medical history, physical exam, and blood tests.

Participants will have urine tests, EKG, and chest x-ray.

Donors will have:

Bone marrow harvest: With anesthesia, marrow is taken by a needle in the hipbone.

OR

Blood collection: They will have several drug injections over 5-7 days. Blood is taken by IV in one arm, circulates through a machine to remove stem cells, and returned by IV in the other arm.

Possible vein assessment or pre-anesthesia evaluation

Recipients will have:

Lung test, heart tests, radiology scans, CT scans, and dental exam

Possible tissue biopsies or lumbar puncture

Bone marrow and a small piece of bone removed by needle in the hipbone.

Chemotherapy 1-2 weeks before transplant day

Donor stem cell donation through a catheter put into a vein in the chest or neck

Several-week hospital stay. They will take medications and may need blood transfusions and additional procedures.

After discharge, recipients will:

Remain near the clinic for about 3 months. They will have weekly visits and may require hospital readmission.

Have multiple follow-up visits to the clinic in the first 6 months, and less frequently for at least 5 years.


Condition or disease Intervention/treatment Phase
Primary T-cell Immunodeficiency Disorders Common Variable Immunodeficiency Immune System Diseases Autoimmune Lymphoproliferative Lymphoproliferative Disorders Drug: Immunosuppression Only Conditioning - Closed with amendment L Drug: Reduced Intensity Conditioning Drug: Myeloablative Conditioning-Closed with amendment L Drug: GVHD Prophylaxis Procedure: Allo BMT Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 224 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
Actual Study Start Date : November 19, 2015
Estimated Primary Completion Date : December 21, 2019
Estimated Study Completion Date : October 21, 2027


Arm Intervention/treatment
Experimental: 1/IOC Arm-Closed with amendment L
Immunosuppression Only Conditioning Arm
Drug: Immunosuppression Only Conditioning - Closed with amendment L
Pentostatin 4 mg/m2 /day IV on days -9 and -5, cyclophosphamide 5 mg/kg orally daily on days -9 through -2 (Closed with amendment L)

Drug: GVHD Prophylaxis
High-dose, post-transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, sirolimus 6 mg on days +5 through +180, and mycophenolate mofetil (MMF) on days +5 through 0, +18, +25, or +35 depending on treatment arm and cohort.

Procedure: Allo BMT
Allogeneic blood or marrow transplantation

Experimental: 2/RIC Arm
Reduced Intensity Conditioning Arm
Drug: Reduced Intensity Conditioning
pentostatin 4 mg/m(2)/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, sirolimus 6 mg on days +5 through +180, and mycophenolate mofetil (MMF) on days +5 through 0, +18, +25, or +35 depending on treatment arm and cohort.

Procedure: Allo BMT
Allogeneic blood or marrow transplantation

Experimental: 3/MAC Arm-Closed with amendment L
Myeloablative Conditioning Arm
Drug: Myeloablative Conditioning-Closed with amendment L
Pentostatin 4 mg/m2/day IV on days -13 and -9, low-dose cyclophosphamide orally daily on days -13 through -6; busulfan IV, pharmokinetically dosed, on days -5, -4, -3, and -2. (Closed with amendment L)

Drug: GVHD Prophylaxis
High-dose, post-transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, sirolimus 6 mg on days +5 through +180, and mycophenolate mofetil (MMF) on days +5 through 0, +18, +25, or +35 depending on treatment arm and cohort.

Procedure: Allo BMT
Allogeneic blood or marrow transplantation

Experimental: 4/RIC-MMF Arm
Reduced Intensity Conditioning with MMF duration de-escalation design
Drug: Immunosuppression Only Conditioning - Closed with amendment L
Pentostatin 4 mg/m2 /day IV on days -9 and -5, cyclophosphamide 5 mg/kg orally daily on days -9 through -2 (Closed with amendment L)

Drug: GVHD Prophylaxis
High-dose, post-transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, sirolimus 6 mg on days +5 through +180, and mycophenolate mofetil (MMF) on days +5 through 0, +18, +25, or +35 depending on treatment arm and cohort.

Procedure: Allo BMT
Allogeneic blood or marrow transplantation




Primary Outcome Measures :
  1. For the RIC : To estimate the aGVHD-free, graft failure-free survival [ Time Frame: +180 after allo BMT ]
    Proportion of patients without GVHD

  2. For the RIC-MMF arm: To determine the shortest duration of MMF that can be safely administered without excessive rates of graft failure or acute grade 3-4 GVHD [ Time Frame: Duration de-escalation design ]
    Shortest duration of MMF


Secondary Outcome Measures :
  1. 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

  2. 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.

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

  4. Event-free survival [ Time Frame: 1 year 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.

  5. Overall survival [ Time Frame: 1 year post transplant ]
    Time from transplant to death of any cause.

  6. Kinetics and durability of engraftment [ Time Frame: days +28, +42, +60, +100, +180, and 1 year 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 lineages pecific donor chimerism [ Time Frame: days +28 and +42 ]
    Median amount of patient who has early chimerism

  8. Secondary graft failure [ Time Frame: 1 year post transplant ]
    Cumulative incidence of secondary graft failure at 1 year post transplant.

  9. Disease free survival [ Time Frame: 1 year post-transplant ]
    Time from transplant to death of any cause or disease relapse.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   4 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA - RECIPIENT:
  • Patients age greater than or equal to 4 through 75 years
  • PID deemed to be of sufficient past severity to warrant allo BMT, by meeting the two criteria below:

    1. PID as defined by monogenetic mutation or, in the absence of a PID-associated genetic mutation, patients with an immune defect potentially amenable to allo BMT who meet the clinical history criteria below may be eligible upon discussion with the PI

      • Mutations should be confirmed in a CLIA-certified laboratory, if such testing is available.
      • Patients without a mutation must be deemed eligible and appropriate for allo BMT by the PI. Some patients may meet the clinical history criteria listed below, but will not be eligible if it is thought that their clinical history is due to a condition apart from an immune defect. In addition, patients with a PID of mild severity, such as those with selective IgA deficiency, may meet at least two of the clinical history criteria, but may be deemed inappropriate for allo BMT by the PI if it is felt that the risks of the procedure outweigh the severity of the disease.
    2. Clinical history of at least two of the following:

      • Life-threatening, organ-threatening, or severely disfiguring infection
      • Protracted or recurrent infections requiring unusually long or repeated courses of antibiotics
      • Infection with an opportunistic organism
      • Chronic elevation in the blood (greater than or equal to 2 documented elevations over a period of 6 months or longer) of a latent virus (EBV, CMV, HHV6, HHV8, etc.)
      • Evidence of immune dysregulation, as manifested by autoimmune disease, atopy, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, granulomas, splenomegaly, or lymphadenopathy
      • Patients with hemophagocytic lymphohistiocytosis or macrophage activation syndrome related to an underlying lymphoma with no other clinical history suggestive of a primary immunodeficiency will not be eligible
      • Hypogammaglobulinemia, dysglobulinemia, or impaired response to vaccination
      • Hematologic malignancy or lymphoproliferative disorder
      • Tissue diagnosis should be confirmed by NCI Department of Pathology, if prior biopsies are available
      • Virus-associated solid tumor malignancy or pre-cancerous lesion
      • Tissue diagnosis should be confirmed by NCI Departmentof Pathology, if prior biopsies are available
  • Availability of at least one 9-10/10 HLA-matched related (excluding an identical twin) or unrelated donor, or an HLA-haploidentical related donor
  • Consensus among the PI, key AIs, and consultants (as necessary) that correction of the patient s immune system through BMT has the potential to improve the patient s health, quality of life, and/or life expectancy, after taking into consideration the patient s existing non-hematopoietic, potentially irreversible organ dysfunction
  • Adequate end-organ function, as measured by:

    • Left ventricular ejection fraction (LVEF) greater than or equal to 40% by 2D echocardiogram (ECHO) or MUGA, or left ventricular shortening fraction greater than or equal to 20% by ECHO for patients receiving RIC or RIC-MMF, or LVEF greater than or equal to 30% if the patient has radiologic evidence of aortic, renal, or coronary artery vasculitis.
    • Pulmonary function tests: DL(co) (corrected for hemoglobin) and FEV(1) greater than or equal to 40% of predicted for the RIC and RIC-MMF arms; or in pediatric patients, 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 values reported in CRIS.
    • Bilirubin less than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or hemolysis) for patients receiving RIC or RIC-MMF; ALT and AST less than or equal to 10 times ULN for patients receiving RIC or RIC-MMF. Patients who are above these bilirubin, ALT, or AST thresholds may be eligible for the RIC or RIC-MMF arms if evaluated by a hepatologist who deems the liver function test abnormalities to be potentially reversible with bone marrow transplant.
    • Estimated creatinine clearance of greater than or equal to 40 mL/min/1.73 m(2), calculated using the Cockcroft-Gault equation for adults and Schwartz formula for pediatric patients, for patients with creatinine levels above the institutional upper limit of normal
  • Adequate central venous access potential
  • Karnofsky or Lansky performance status of greater than or equal to 60% or ECOG performance status of 2 or less
  • Ability of subject 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 BMT. 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: Patients with malignancy are to be referred in remission for evaluation, except in cases of virus-associated malignancy who may be referred at any time. Should a patient have progressive disease or a donor becomes unavailable after enrollment, the patient will be referred back to his/her primary hematologist-oncologist for treatment. If this course of action is not in the best interest of the patient according to the clinical judgment of the PI, then the patient may receive standard treatment for the malignant disease under the current study, although this should only occur as a bridge to transplant. If under either of these settings, it becomes apparent that the patient will not be able to proceed to transplant, then he/she must come off the study. Patients 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:

  • Patients 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 BMT.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (cyclophosphamide, busulfan, pentostatin, sirolimus, MMF, G-CSF) used in the study
  • Active psychiatric disorder which may compromise compliance with the transplant protocol, or which does not allow for appropriate informed consent
  • Active central nervous system (CNS) involvement by malignancy, except in cases of virus-associated malignancies with CNS involvement in which case the patient may benefit from the transplant to control the malignancy.
  • MAGT1 mutation and active need to take anti-platelet agents and/or therapeutic anti-coagulation that cannot be interrupted during aplasia.
  • HIV positive or other acquired immunodeficiency that, as determined by the PI, interferes with the assessment of PID severity and/or the attribution of clinical manifestations of immunodeficiency to a PID.

Inclusion Criteria (Related Donor):

-Related donor deemed suitable and eligible and willing to donate per clinical evalations 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 on 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. 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.

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/.


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): NCT02579967


Contacts
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Contact: Jennifer A Kanakry, M.D. (240) 760-6172 jennifer.kanakry@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
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:
Publications:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02579967     History of Changes
Other Study ID Numbers: 160003
16-C-0003
First Posted: October 20, 2015    Key Record Dates
Last Update Posted: August 21, 2019
Last Verified: August 9, 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