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Allogeneic Hematopoietic Stem Cell Transplant for People With Primary Immunodeficiency Diseases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04339777
Recruitment Status : Recruiting
First Posted : April 9, 2020
Last Update Posted : November 24, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

During a transplant, blood stem cells from one person are given to someone else. The cells grow into the different cells that make up the immune system. This can cure people with certain immunodeficiencies. But transplant has many risks and complications.

Objective:

To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them.

Eligibility:

People ages 4-69 for whom a primary immunodeficiency (PID) or Primary Immune Regulatory Disorder (PIRD), has caused significant health problems and either standard management has not worked or there are no standard management options, along with their donors

Design:

Donors will be screened under protocol 01-C-0129. They will donate blood or bone marrow.

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

CT or PET scans

Before transplant, participants will have dental and eye exams. They will have a bone marrow biopsy. For this, a needle will be inserted through the skin into the pelvis to remove marrow.

Participants will be hospitalized before their transplant. They will have a central catheter put into a vein in their chest or neck. They will get medications through the catheter to prevent complications. Participants will get stem cells through the catheter. They will stay in the hospital for at least 4 weeks. They will give blood, urine, bone marrow, and stool samples. They may need blood transfusions. They may need more scans. They will take more medications.

Participants will have visits on days 30, 60, 100, 180, and 360, and 24 months after the transplant. Then they will have visits once a year for about 5 years


Condition or disease Intervention/treatment Phase
Lymphoproliferative Disorders Autoimmune Lymphoproliferative Immune System Diseases Common Variable Immunodeficiency Primary T-cell Immunodeficiency Disorders Drug: Busulfan test dose Drug: Fludarabine Drug: Busulfan Drug: Alemtuzumab Radiation: Total body Irradiation Procedure: Allogeneic HSCT Drug: Tacrolimus (Tacro) Drug: Mycophenolate mofetil (MMF) Drug: Cyclophosphamide (Cytoxan) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immunodeficiency Diseases
Actual Study Start Date : September 22, 2020
Estimated Primary Completion Date : October 1, 2024
Estimated Study Completion Date : November 30, 2025


Arm Intervention/treatment
Active Comparator: Arm A
Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab
Drug: Busulfan test dose
0.8 mg/kg IV infusion over 2 hours

Drug: Fludarabine
40 mg/m2 IV infusion over 30 min once daily for 4 days

Drug: Busulfan

AUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 10/10 Matched Related and Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 4 days (-6, -5, -4, and -3).

For Intermediate Intensity Arm, the busulfan dose will be given for 3 days (-6,-5, and -4).

For Low Intensity Arm, the busulfan dose will be given for 2 days on days (-6 and -5). 9/10 HLA Matched Related or Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 3 days (-6,

-5, and -4). For the the Intermediate Intensity Arm, the busulfan dose will be given for 2 days (-6 and -5).

For the Low Intensity Arm, the busulfan dose will be given for 1 day on day (-6).


Drug: Alemtuzumab
Alemtuzumab will be given if there is evidence of immune dysregulation. 0.03 mg/kg IV on day -11, 0.1 mg/kg IV on day -10, and 0.2 mg/kg IV on days -9 and -8

Procedure: Allogeneic HSCT
Stem cell transplant

Drug: Tacrolimus (Tacro)
Tacrolimus 0.02 mg/kg IV continuous infusion over 24 hours starting on day +5

Drug: Mycophenolate mofetil (MMF)
Mycophenolate mofetil 15 mg/kg IV over 2 hours BID starting on day +5 will continue until Approximately+35 (+/- two days)

Drug: Cyclophosphamide (Cytoxan)
Cyclophosphamide: 50 mg/kg IV once daily over 2 hours on days +3 and +4, dosed according to ideal body weight

Active Comparator: Arm B
Intermediate Intensity Conditioning with or without Alemtuzumab
Drug: Busulfan test dose
0.8 mg/kg IV infusion over 2 hours

Drug: Fludarabine
40 mg/m2 IV infusion over 30 min once daily for 4 days

Drug: Busulfan

AUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 10/10 Matched Related and Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 4 days (-6, -5, -4, and -3).

For Intermediate Intensity Arm, the busulfan dose will be given for 3 days (-6,-5, and -4).

For Low Intensity Arm, the busulfan dose will be given for 2 days on days (-6 and -5). 9/10 HLA Matched Related or Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 3 days (-6,

-5, and -4). For the the Intermediate Intensity Arm, the busulfan dose will be given for 2 days (-6 and -5).

For the Low Intensity Arm, the busulfan dose will be given for 1 day on day (-6).


Drug: Alemtuzumab
Alemtuzumab will be given if there is evidence of immune dysregulation. 0.03 mg/kg IV on day -11, 0.1 mg/kg IV on day -10, and 0.2 mg/kg IV on days -9 and -8

Radiation: Total body Irradiation
200 cGy Transplant Day -1 (Only for 9/10 HLA Matched Related or Unrelated Donor Recipients )

Procedure: Allogeneic HSCT
Stem cell transplant

Drug: Tacrolimus (Tacro)
Tacrolimus 0.02 mg/kg IV continuous infusion over 24 hours starting on day +5

Drug: Mycophenolate mofetil (MMF)
Mycophenolate mofetil 15 mg/kg IV over 2 hours BID starting on day +5 will continue until Approximately+35 (+/- two days)

Drug: Cyclophosphamide (Cytoxan)
Cyclophosphamide: 50 mg/kg IV once daily over 2 hours on days +3 and +4, dosed according to ideal body weight




Primary Outcome Measures :
  1. primary graft failure/rejection [ Time Frame: between day +21 to +42 ]
    Cumulative incidence of primary graft failure/rejection between day 21to +42 post transplant.


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

  2. 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.

  3. Incidence of Acute Graftversus-host disease [ Time Frame: 100 days post transplant ]
    Cumulative incidence of acute graft versus host disease at day 100 post transplant

  4. Incidence of Chronic Graftversus-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.

  5. Improvement of the clinical phenotype [ Time Frame: 1 and 2 years post transplant ]
    Cumulative improvement of clinical phenotype at 1 and 2 years post transplant.

  6. Reversal of the immunological abnormalities [ Time Frame: 1 and 2 years post transplant ]
    Cumulative correction of disease-specific immunological abnormalities (PID)at 1 and 2 years post transplant.

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

  8. 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 69 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Age >= 4 years and <= 69 yo with Weight >=12 kilograms
  • Mutation in a known monogenic Primary Immunodeficiency Disease (PID) gene or Primary Immune Regulatory Disorder (PIRD) performed by a CLIA certified laboratory, who have failed standard medical management, or when no standard medical management is available. OR
  • Patients without a known PID or PIRD mutation may be eligible if they have a clinical history that is characteristic of an individual with an immune defect including a history of infections requiring prolonged courses of therapy or evidence of immune dysregulation manifested by autoimmune/autoinflammatory disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired response to vaccination. A virally-driven malignancy alone will also constitute basis for inclusion.
  • Availability of a 10/10 or 9/10 HLA-matched related or unrelated donor (if the mismatch is at DQ this will be considered an 8/8 matched donor), or a haploidentical related donor.
  • Adequate central venous access potential
  • Karnofsky or Lansky performance status of >= 40%
  • Adequate end-organ function, as measured by:

    • Left ventricular ejection fraction > 40%, preferably by 2-D echocardiogram (ECHO) obtained within 60 days prior to enrollment.
    • Creatinine: Adult patients: <= 2.0 mg/dl and creatinine clearance >=30 ml/min; Pediatric patients (<18 years old): creatinine < 1.5 mg/dL and a creatinine clearance, using the Schwartz Formula > 30 mL/min/1.73m^2.
    • Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST 5 times upper limit of normal.
    • Pulmonary function tests: FEV1 > 30% and DLCO >30%. Children who are unable to have DLCO assessed due to age, are still eligible if no evidence of dyspnea at rest and no need for supplemental oxygen.
  • Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document. For subjects <18 years old, their legal guardian must give informed consent. Pediatric patients will provide assent.
  • 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.
  • Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH, for a minimum of 100 days after transplant or longer, if there are complications. If outpatient in the first 100 days after transplant, patient must commit to having an adult caregiver with them at all times.

Exclusion Criteria

  • 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 HCT.
  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (steroids, cyclophosphamide, busulfan, sirolimus, 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
  • Pregnant women are excluded from this study because the study agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding should be discontinued if the mother is treated with the study agents.
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

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): NCT04339777


Contacts
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Contact: Dennis D Hickstein, M.D. (240) 760-6169 hicksted@mail.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      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Dennis D Hickstein, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04339777    
Other Study ID Numbers: 200070
20-C-0070
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: November 24, 2020
Last Verified: November 20, 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 National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Autoimmunity
Haploidentical
Opportunistic Infection
Immune Dysregulation
Congenital
Additional relevant MeSH terms:
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Lymphoproliferative Disorders
Immunologic Deficiency Syndromes
Immune System Diseases
Common Variable Immunodeficiency
Disease
Pathologic Processes
Lymphatic Diseases
Immunoproliferative Disorders
Mycophenolic Acid
Cyclophosphamide
Busulfan
Fludarabine
Alemtuzumab
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents