NCT05463133

Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease (CGD) With an Alemtuzumab, Busulfan and TBI-based Conditioning Regimen Combined With Cytokine (IL-6, +/- IFN-gamma) Antagonists

Phase I/II Study Using Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease With an Alemtuzumab, Busulfan and TBI-based Conditioning Regimen Combined With Cytokine (IL-6, +/- IFN-gamma) Antagonists

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) · NIH
• Sex: All
• Age: 4 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

Background: Chronic granulomatous disease (CGD) affects the immune system. People with CGD are more likely to get infections. Drugs can help control infections, but these treatments can cause side effects including kidney failure and deafness. Stem cell transplants can cure CGD, but these don t always work. Objective: To find out if a different drug treatment can improve the success rates of stem cell transplants in people with CGD. Eligibility: People aged 4-65 years with CGD. Design: Participants will undergo screening. They will have a physical exam. They will have blood and urine tests and tests of their heart function and breathing. They will have imaging scans. They will have a bone marrow biopsy; a needle will be inserted into their hip to draw a sample of tissue from the bone. A tube called a catheter will be placed into a vein in the participant s chest. This catheter will remain in place for the transplant and recovery period. Blood for tests can be drawn from the catheter, and medications and the stem cells can be administered through it. Participants will be in the hospital for either 10 or 21 days to receive 3 or 4 drugs before the transplant. They will get 2 doses of total body radiation on the same day. Participants will receive donor stem cells through the catheter. They will remain in the hospital for 6 weeks afterward. Participants will visit the clinic 2 to 3 times per week for 3 months after discharge. Follow-up visits will continue for 5 years.

Detailed description

Chronic Granulomatous Disease (CGD) is an inherited disorder resulting from a failure to produce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, necessary for protection against a number of infectious organisms. Patients are subject to recurrent infections and inflammatory complications. The current management of these patients is limited to close surveillance for infections, administration of prophylactic antimicrobials, and rapid and aggressive treatment of suspected and documented infections with broad-spectrum antibiotics. Although often effective, these treatments can require long hospitalizations, impacting the overall quality of life significantly and leading to significant morbidity, such as renal failure and deafness. CGD patients have autoinflammation that may manifest as inflammatory bowel disease, hypoxic lung inflammation, and/or liver nodular regenerative hyperplasia with venopathy as examples. Currently the only available cure for these disorders is bone marrow transplantation, which preferentially uses a human leukocyte antigen (HLA)-matched related sibling as the donor (allogeneic stem cell transplantation). However, as only 30% of participants in the general population have an HLA-matched related sibling, allogeneic related transplantation is often not an option, resulting in the need for matched unrelated donor (MUD) transplantation. The National Marrow Donor Program (NMDP) serves as both a national registry of volunteers who are willing to donate progenitor cells to eligible recipients as well as a repository of cord blood products. Despite continued improvement in the use of transplantation schemas - including the development of nonmyeloablative regimens - there remain significant morbidity and mortality associated with transplantation, in particular graft versus host disease (GvHD) and graft rejection. CGD with severe autoinflammation manifested as C-reactive protein (CRP) \>= 100 milligrams per milliliter (mg/mL) has been a significant risk factor for mortality due to severe engraftment syndrome, and thus patients with elevated CRPs have not been eligible for prior transplant protocols. In addition, despite improving engraftment rates, there continues to be mixed chimerism and late graft loss in CGD participants despite a variety of conditioning regimens being used at various centers. In our most recent protocol, we have continued to have a low incidence of graft versus host disease and improved engraftment, but still could see improvement in graft stability. Thus, in order to improve outcomes with participants with elevated CRPs as well as improve overall engraftment, we are building on our prior regimens by targeting the inflammatory cytokines that appear to be involved in graft failure and engraftment syndrome. Participants with a CRP of less than 100 mg/mL will be pretreated with a dose of tocilizumab, an anti-IL6 monoclonal antibody. Participants with a CRP of greater than 100 mg/mL will be pretreated with 2 doses of tocilizumab as well as an inhibitor of interferon-gamma in order to decrease the inflammation that has been seen in these participants with engraftment. Otherwise, the conditioning regimen will be similar to maintain the low rates of GvHD that we have seen to date.

Conditions

• Chronic Granulomatous Disease

Interventions

Type	Name	Description
DRUG	Sirolimus	Post transplant drug - Immunosuppressant to prevent donor peripheral blood stem cell rejection and graft versus host disease. This is a well studied drug, and is not under an IND.
DRUG	Cyclophosphamide	Post transplant drug - cyclophosphamide give to prevent graft versus host disease. This is a well studied drug and s not under an IND.
DRUG	Alemtuzumab	Transplant Conditioning Drug - Monoclonal antibody that targets recipient and donor T-cells to prevent graft versus host disease. Not an IND. This is a well-studied drug, and is not under an IND.
DRUG	Busulfan	Transplant Conditioning Drug - Chemotherapy to create space in the patient's bone marrow so that the donor peripheral blood stem cells can repopulate in the patient's bone marrow. This is a well studied drug, and is not under IND.
BIOLOGICAL	Pheripheral blood stem cells	Donor peripheral blood stem cells either matched unrelated donors or matched related relative to replace the patient's immune cells with functional immune cells. The peripheral blood stem cells are not regulated by the FDA.
DRUG	Emapalumab-Izsg	Transplant conditioning drug for High Risk Group only - An interferon gamma blocking antibody used to prevent inflammation/engraftment syndrome post HSC transplant.
DRUG	Tociluzumab	Transplant Conditioning Drug - An interleukin-6 (IL-6) receptor antagonist used to decrease Chronic Granulomatous Disease (CGD) inflammation during the HSC transplant process.
DRUG	Total Body Irradiation	Transplant Conditioning - Total Body Irradiation (300 cGy in fractionated doses) to create space n the subject's bone marrow so that the donor peripheral blood stem cells can repopulate in the subject's bone marrow.

Timeline

• Start date: 2022-07-08
• Primary completion: 2032-12-31
• Completion: 2032-12-31
• First posted: 2022-07-18
• Last updated: 2026-04-01

Locations

1 site across 1 country: United States