Clinical Trial Details
— Status: Suspended
Administrative data
NCT number |
NCT05027945 |
Other study ID # |
10000404 |
Secondary ID |
000404-C |
Status |
Suspended |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
February 23, 2023 |
Est. completion date |
July 1, 2026 |
Study information
Verified date |
June 13, 2024 |
Source |
National Institutes of Health Clinical Center (CC) |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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....
Description:
Background:
- In 2019, investigators at the National Institutes of Health defined a new disease
syndrome named VEXAS: Vacuoles in bone marrow cells, E1 enzyme mutations, X-linked,
Autoinflammatory, Somatic syndrome. This syndrome is characterized by inflammatory and
hematologic features and is frequently accompanied by marrow dysplasia, progressive bone
marrow failure, and in some cases, the development of overt myelodysplastic syndrome
(MDS) or other myeloid neoplasms. Somatic mutations are present at methionine 41 in
UBA1, an X-linked gene encoding the major E1 ubiquitin activating enzyme that initiates
the majority of cellular ubiquitylation.
- The inflammatory features of VEXAS include fever, pulmonary infiltrates, skin lesions,
ear and nose chondritis, musculoskeletal involvement, and elevated inflammatory markers.
The hematologic features include cytopenia, characteristic vacuoles in myeloid and
erythroid precursors cells, and dysplastic bone marrow. Patients included in the initial
description of the syndrome fulfill clinical or classification criteria for both
inflammatory diseases (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa,
giant cell arteritis) and hematologic conditions (MDS, myeloid neoplasms or plasma cell
dyscrasia). The inflammatory features of VEXAS are refractory to treatment other than
high doses of glucocorticoids. Increased mortality and frequent morbidity are common in
VEXAS secondary to the disease and treatment-related complications. The clinical
manifestations of VEXAS are time-dependent. Systemic inflammation typically precedes
progressive bone marrow failure with or without the development of hematologic
malignancies leading to death. Escalating doses of glucocorticoids are typically
administered to control the refractory, progressive features of systemic inflammation.
Worsening cytopenias often require transfusion support.
- The discovery of hematologic mosaicism as the genetic driver of
rheumatologic/hematologic syndromes defines a novel class of diseases, termed
hematoinflammatory diseases (HINDS), and it raises the possibility that therapies aimed
at eradicating these clones may be efficacious in this patient population.
Objectives:
Primary Objectives:
- To determine whether allogeneic hematopoietic stem cell transplantation (HSCT) results
in sustained donor engraftment at day 100 and one-year post-HSCT.
- To determine whether allogeneic HSCT results in reversal of the clinical phenotype of
VEXAS at one year and two years post-HSCT without requiring interval prednisone at >=
0.5 mg/kg per day for reasons other than graft-versus-host disease (GVHD).
Eligibility:
- Recipients ages 18-75 year-old with or without a somatic mutation in UBA1 who have: 1)
the clinical phenotype for VEXAS with refractory cutaneous, pulmonary, musculoskeletal,
and/or other recurrent acute inflammatory manifestations, and 2) require >= 0.5 mg/kg
per day of prednisone for inflammatory manifestations OR have cytopenia (transfusion
dependent anemia, transfusion dependent thrombocytopenia/platelets <75,000, neutropenia
<1,000/microL) or myeloid neoplasm (by WHO criteria) or being intolerant or refractory
to use steroids.
- Have an 8/8 or 7/8 HLA-matched related or unrelated donor, or a haploidentical related
donor.
Design:
-For Recipients with 8/8 HLA Matched Donors:
Participants will receive reduced intensity conditioning with the following regimen:
fludarabine 40 mg/m^2 IV once daily for four days on days -6, -5, -4, -3 and Busulfan IV for
three days on days -6, -5, -and -4 followed by HSCT on day 0. The busulfan dose will be based
on pharmacokinetic levels from the test dose and/or real time PKs and will be targeted to an
AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (2.8 - 3.2 mg/kg IV per day may be used
alternatively).
-For Recipients with 7/8 HLA Matched Donors or Haploidentical Related Donors:
Participants will receive reduced intensity conditioning with the following regimen:
fludarabine 30 mg/m^2 IV once daily for five days on days -6, -5, -4, -3, and -2,
cyclophosphamide 14.5 mg/kg for two days on days -6 and -5, 200 cGy total body irradiation
(TBI) on day -1, busulfan IV once daily for two days on days -4 and -3, and HSCT on day 0.
The busulfan dose will be based on pharmacokinetic levels from the test dose and/or real time
PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52- 65 mg*h/L) (2.8 -3.2
mg/kg IV per day may be used alternatively).
-For Post-Transplant GVHD Prophylaxis:
Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV
once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to
approximately day +35 and sirolimus from day +5 to approximately day +180.