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A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome

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: NCT05027945
Recruitment Status : Recruiting
First Posted : August 31, 2021
Last Update Posted : September 23, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Allogeneic hematopoietic stem cell transplant involves taking blood stem cells from a donor and giving them to a recipient. The transplants are used to treat certain diseases and cancers. Researchers want to see if the transplant can treat VEXAS Syndrome.

Objective:

To see if stem cell transplants can be successfully performed in people with VEXAS and even improve the disease.

Eligibility:

People ages 18-75 who have VEXAS Syndrome that has caused significant health problems and standard treatment either has not worked or is not available.

Design:

Participants will be screened with:

Physical exam

Medical review

Blood and urine tests

Heart and lung function tests

Bone marrow biopsy

Participants will have a chest x-ray. They will have an imaging scan of the head, chest, abdomen, pelvis, and sinus. They will have a bone density scan. They will have a dental exam and eye exam. They will meet with specialists. They will repeat some screening tests.

Participants will be admitted to the NIH hospital. They have a central venous catheter put into a vein in the chest or neck. They will receive drugs to prepare their bone marrow for the transplant. They may have total body irradiation. They will receive the donor stem cells through the catheter. They will get other drugs to prevent complications and infections. After discharge, they must stay in the DC area for 3 months for weekly study visits.

Participants will have study visits 30, 60, 100, 180, 210, 240, 300, and 360 days later. After that, they will have yearly visits for 2 years and then be contacted yearly by phone....


Condition or disease Intervention/treatment Phase
Immunodeficiency Hematopoietic Stem Cell Transplantation Drug: Post-Transplant Cyclophosphamide (PTCY) Drug: Cyclophosphamide (CY) Drug: Fludarabine Radiation: Total Body Irradiation (TBI) Drug: Busulfan Drug: Sirolimus Drug: Mycophenolate mofetil (MMF) Drug: Busulfan test dose Procedure: Allogeneic HSCT Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 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 Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome
Estimated Study Start Date : September 28, 2022
Estimated Primary Completion Date : July 1, 2025
Estimated Study Completion Date : July 1, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
Reduced intensity regimen (Fludarabine, busulfan)+HSCT+GVHD prophylaxis
Drug: Post-Transplant Cyclophosphamide (PTCY)
Post-Transplant Cyclophosphamide: 50 mg/kg IV daily over 2 hours on days +3 and +4, dosed according to ideal body weight

Drug: Fludarabine
40 mg/m2 IV over 30 mins daily For 8/8 Matched Related or Unrelated Donor Fludarabine dose will be on days -6, -5, -4, and -3 For 7/8 Matched Related or Unrelated or Haploidentical Donor Fludarabine dose will be on days -6, -5, -4, -3, and -2

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 8/8 Matched Related or Unrelated Donor Busulfan dose will be on days -6, -5, and -4 For 7/8 Matched Related or Unrelated or Haploidentical Donor Busulfan dose will be on days -4 and -3

Drug: Sirolimus
Sirolimus: on day +5 5mg PO loading dose q4h for 3 doses, then 5 mg PO q24h starting on day +6

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

Drug: Busulfan test dose
0.8 mg/kg IV over 2 hours

Procedure: Allogeneic HSCT
stem cell transplant on day 0

Experimental: Arm B
Reduced intensity regimen (Fludarabine, low dose cyclophosphamide, 200cGY TBI, busulfan)+HSCT+GVHD prophylaxis
Drug: Post-Transplant Cyclophosphamide (PTCY)
Post-Transplant Cyclophosphamide: 50 mg/kg IV daily over 2 hours on days +3 and +4, dosed according to ideal body weight

Drug: Cyclophosphamide (CY)
For 7/8 Matched Related or Unrelated or Haploidentical Donor, prior to transplant 14.5 mg/kg IV daily on days -6 and -5

Drug: Fludarabine
40 mg/m2 IV over 30 mins daily For 8/8 Matched Related or Unrelated Donor Fludarabine dose will be on days -6, -5, -4, and -3 For 7/8 Matched Related or Unrelated or Haploidentical Donor Fludarabine dose will be on days -6, -5, -4, -3, and -2

Radiation: Total Body Irradiation (TBI)
For 7/8 Matched Related or Unrelated or Haploidentical Donor, 200cGy on day -1

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 8/8 Matched Related or Unrelated Donor Busulfan dose will be on days -6, -5, and -4 For 7/8 Matched Related or Unrelated or Haploidentical Donor Busulfan dose will be on days -4 and -3

Drug: Sirolimus
Sirolimus: on day +5 5mg PO loading dose q4h for 3 doses, then 5 mg PO q24h starting on day +6

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

Drug: Busulfan test dose
0.8 mg/kg IV over 2 hours

Procedure: Allogeneic HSCT
stem cell transplant on day 0




Primary Outcome Measures :
  1. Reversal of clinical phenotype of VEXAS [ Time Frame: +1 and +2 years post HSCT ]
    fraction of subjects who achieve complete clinical response without use of additional glucocorticoid therapy and without steroid-sparing therapy

  2. Sustained donor engraftment [ Time Frame: day +100 and +1 year post HSCT ]
    defined as neutrophil recovery with ANC = 500/mm^3 for 3 consecutive days associated with > 50% T-cell and myeloid cell donor chimerism at day 100 and one year post-HSCT


Secondary Outcome Measures :
  1. Safety of allo HSCT [ Time Frame: +1, +2 and +3 years post HSCT ]
    Transplant-related toxicity will include if allogeneic HSCT in participants with VEXAS results in the absence of secondary graft failure. The fraction of participants who have secondary graft failure will be reported along with a 95% two-sided confidence interval, separately by cohort.

  2. incidence of grade III-IV acute GVHD and moderate to severe chronic GVHD [ Time Frame: +1 and +2 years post HSCT ]
    group comparison of participants with an 8/8 HLA matched related or unrelated donor compared to group of participants with 7/8 HLA matched related or unrelated donor or haploidentical donor. Reported with 95% two-sided confidence intervals. The fractions will also be reported separately by cohort using simple estimates along with 95% two-sided confidence intervals. In addition cumulative incidence curves along with a 95% two-sided confidence interval.

  3. Overall survival and event free survival [ Time Frame: +1, +2 and +3 years post HSCT ]
    Overall and event free survival will be determined using Using the Kaplan-Meier method, along with the median value and the 95% confidence interval at the median, separately by cohort.



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:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Non-disease related

  • Age >= 18-year-old and <= 75-year-old
  • Availability of an 8/8 or 7/8 HLA-matched related or unrelated donor, or a haploidentical related donor
  • Karnofsky performance status of >= 40%
  • Adequate end-organ function, defined as follow:

    1. Left ventricular ejection fraction > 35%, preferably by 2-D echocardiogram (ECHO) obtained within 60 days prior to treatment initiation.
    2. Creatinine <= 2.0 mg/dl and creatinine clearance >= 30 ml/min;
    3. Serum conjugated bilirubin < 3.0 mg/dl; serum ALT and AST <= 5 times upper limit of normal.
  • Pulmonary function tests: FEV1 and DLCO >30%
  • Ability of subject to understand and the willingness to sign a written informed consent document.
  • 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) at the 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, live within 2 hours drive from 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, participant must commit to having an adult caregiver with them at all times.

Disease related

  • Somatic mutation in UBA1 performed by a CLIA or CAP certified laboratory. NOTE: Participants without a mutation or unknown mutation status may be eligible if they have a clinical history that is characteristic of an individual with VEXAS syndrome including two or more of a-e below.
  • Inflammatory clinical phenotype for VEXAS syndrome with at least one VEXAS disease manifestation below:

    1. constitutional symptoms including fevers, fatigue, and weight loss
    2. cutaneous symptoms of VEXAS including biopsy proven neutrophilic dermatosis, cutaneous vasculitis, periorbital inflammation
    3. pulmonary symptoms of VEXAS with pulmonary infiltrates, pleural effusion
    4. musculoskeletal or cartilaginous involvement including inflammatory arthritis, ear chondritis, and nasal chondritis
    5. inflammatory disease in other major organ systems including cardiac, gastrointestinal, ocular, etc.
  • Presence of cytopenia defined as at least one of the following:

    i. Absolute neutrophil count <=1000/ L

ii. platelet count <= 75,000/ L or platelet transfusion dependence (at least 4 platelet transfusions in the 8 weeks prior to study entry

iii. hemoglobin <= 10.0g/dL or red cell transfusion-dependence (at least 4 units of PRBCs in the 8 weeks prior to treatment initiation) or meeting criteria for myeloid neoplasm (MN) by WHO criteria

-Participants who have failed standard medical management (requiring >= 0.5mg/kg per day of prednisone for the above listed inflammatory condition or intolerance or refractory to use of corticosteroids and/or steroid sparing medications as well as biological response modifiers over the last 6 months), or when no standard medical treatment is available.

EXCLUSION CRITERIA:

  • HCT Comorbidity Index >= 5
  • Participants with multiple myeloma. Note: participants with monoclonal gammopathy of unknown significance will not be excluded)
  • Participants who are receiving any other investigational agents within the last 30 days before treatment initiation.
  • HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • 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
  • 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 or social situations (as determined by a licensed master social worker) that would limit compliance with study requirements.
  • Presence of active uncontrolled infections that in the opinion of the PI would make it unsafe to proceed with transplantation
  • Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol

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): NCT05027945


Contacts
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Contact: Bhavisha A Patel, M.D. (301) 402-3477 bhavisha.patel@nih.gov
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)
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05027945    
Other Study ID Numbers: 10000404
000404-C
First Posted: August 31, 2021    Key Record Dates
Last Update Posted: September 23, 2022
Last Verified: July 20, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGAP.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immune Dysregulation
Haploidentical
hematoinflammatory diseases
Myelodysplastic Syndromes
Autoimmune Disorders
Additional relevant MeSH terms:
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Syndrome
Disease
Pathologic Processes
Mycophenolic Acid
Sirolimus
Cyclophosphamide
Busulfan
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Antifungal Agents