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

NCT05463133 | Recruiting Phase 1

• 2 other identifiers: 10000977000977-I
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Chronic Granulomatous Disease

Keywords

HLA Matched Related Donor; Matched Unrelated Donor; The National Marrow Donor Program

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  Alive at 1 years post-transplant.

  1 years post-transplant.

Secondary Outcomes (5)

• To assess the infection rates in the setting of Alemtuzumab (Campath-1H) and post-transplant cyclophosphamide with the addition of an Il-6 antagonist and TNF inhibitor.

  Day 100, 6 months, 1 and/or 2 years post BMT

• To assess kinetics of engraftment

  Day +14, +30, +60, +100, 6 month and 1 year post transplant

• Improve eligibility for allogeneic transplantation.

  Eligibility determination for protocol enrollment

• Engraftment without GvHD

  Day 100, 6 months, and/or 1 year post BMT

• Decreased engraftment syndrome.

  30 days post transplant.

Study Arms (2)

Arm 1 / Group 1 Standard Risk

ACTIVE COMPARATOR

Group 1 (Standard group) will receive tociluzumab at Day -10, Alemtuzumab on Day -9,-8,-7,-6,-5; Busulfan on Day -4, and -3, TBI, matched donor PBSC infusion, and Post transplant Cyclophosphamide.

Drug: Sirolimus; Drug: Cyclophosphamide; Drug: Alemtuzumab; Drug: Busulfan; Biological: Pheripheral blood stem cells; Drug: Tociluzumab; Drug: Total Body Irradiation

Arm 2 / Group 2 High Risk.

EXPERIMENTAL

Group 2 (High risk group will receive tociluzumab at day -24, a repeat dose at day -19, Alemtuzumab at day -9,-8,-7,-6,-5; Busulfan at day -4 and -3, Emapalumab at Day -1, matched donor PBSC infusion, and post transplant cyclophosphamide at Day +3 and +4

Drug: Sirolimus; Drug: Cyclophosphamide; Drug: Alemtuzumab; Drug: Busulfan; Biological: Pheripheral blood stem cells; Drug: Emapalumab-Izsg; Drug: Tociluzumab

Interventions

Cyclophosphamide DRUG

Post transplant drug - cyclophosphamide give to prevent graft versus host disease. This is a well studied drug and s not under an IND.

Arm 1 / Group 1 Standard Risk; Arm 2 / Group 2 High Risk.

Alemtuzumab DRUG

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.

Arm 1 / Group 1 Standard Risk; Arm 2 / Group 2 High Risk.

Busulfan DRUG

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.

Arm 1 / Group 1 Standard Risk; Arm 2 / Group 2 High Risk.

Tociluzumab DRUG

Transplant Conditioning Drug - An interleukin-6 (IL-6) receptor antagonist used to decrease Chronic Granulomatous Disease (CGD) inflammation during the HSC transplant process.

Arm 1 / Group 1 Standard Risk; Arm 2 / Group 2 High Risk.

Sirolimus DRUG

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.

Arm 1 / Group 1 Standard Risk; Arm 2 / Group 2 High Risk.

Pheripheral blood stem cells BIOLOGICAL

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.

Arm 1 / Group 1 Standard Risk; Arm 2 / Group 2 High Risk.

Emapalumab-Izsg DRUG

Transplant conditioning drug for High Risk Group only - An interferon gamma blocking antibody used to prevent inflammation/engraftment syndrome post HSC transplant.

Arm 2 / Group 2 High Risk.

Total Body Irradiation DRUG

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.

Arm 1 / Group 1 Standard Risk

Eligibility Criteria

• Age: 4 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all the following criteria:
• Must have the ability to comprehend and a willingness to sign the informed consent. For pediatric patients, must have a parent/guardian who can sign consent if the donor is a minor; assent will be obtained from minors as appropriate.
• Must have confirmed diagnosis of CGD.
• Must have sufficient complications from underlying disease to warrant undergoing transplantation (either a history of or ongoing inflammation/CGD-related autoimmunity OR a CGD-related infection while on prophylaxis) OR have a Quartile 1 or 2 residual oxidase production level.
• Ages 4 years-65 years.
• HLA-matched family donor graft or an HLA-matched unrelated PBSC graft (10/10 or 9/10 mismatch) available.
• Must be human immunodeficiency virus (HIV) negative.
• When discharged from the hospital the participant must be able to stay within 1 hour s travel of the NIH for the first 3 months after transplantation.
• Must have a family member or other designated care provider to assist with care during the post-transplant period when the patient is in the outpatient setting.
• Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance with NIH 200 'NIH Durable Power of Attorney for Health Care Decision Making.'
• Females of child-bearing potential must agree to consistently use one form of contraception from 1 month prior to study entry and for at least 1 year post transplant. Male participants must agree to consistently use contraception for 1 year post transplant. Acceptable forms of contraception are:
• Contraceptive pills or patch, Norplant \[Registered\], Depo-Provera \[Registered\], or other FDA-approved contraceptive method.
• Male partner has previously undergone a vasectomy.
• Male participants will be advised to consistently use contraception throughout study participation and for 3 months post-transplant.
• Stated willingness to comply with all study procedures and is available for protocol visits for the duration of the study when possible.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Ejection fraction of less than 30% by echocardiography.
• Forced expiratory volume (FEV1%) of less than 35% and/or an adjusted diffusing capacity of lung of carbon monoxide (adj DLCO) of less than 30%.
• Transaminases \>5x upper limit of normal based on the individual s clinical situation and at the discretion of the investigator.
• Psychiatric disorder or mental deficiency severe enough as to make compliance with the HSCT treatment unlikely, and/or to make regulatorily and legally effective informed consent impossible.
• Major anticipated illness or organ failure incompatible with survival from allogeneic peripheral blood stem cell (AlloPBSC) transplant.
• Pregnant or lactating.
• Uncontrolled seizure disorder per principal investigator (PI) discretion.
• Individuals older than 65 years are excluded. It is known from standard transplantation that these individuals have a higher risk of morbidity and mortality related to transplantation. Given the investigational nature of this protocol, the risk-benefit ratio is not warranted to include these individuals at this time.
• Active TB infection.
• Any condition or circumstance that the PI feels would create difficulty in maintaining compliance with the requirements of this protocol.
• Individuals who are not willing to submit their information as part of the alemtuzumab (Campath \[Registered\]) Distribution Program application or participants whom the Distribution Program committee has determined are not qualified to receive alemtuzumab.
• NOTE: Alemtuzumab (Campath-1H) (intravenous \[IV\] formulation) is no longer distributed commercially. To receive product, the physician must contact the program for the patient. If the patient is not willing to consent to submit their info (demographics, contact information, and rationale for use) to the program such that we can obtain the drug, then we cannot proceed with conditioning; therefore no transplant will occur on this protocol. http://www.campath.com/

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (3)

• Parta M, Kelly C, Kwatemaa N, Theobald N, Hilligoss D, Qin J, Kuhns DB, Zerbe C, Holland SM, Malech H, Kang EM. Allogeneic Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: a Single-Center Prospective Trial. J Clin Immunol. 2017 Aug;37(6):548-558. doi: 10.1007/s10875-017-0422-6. Epub 2017 Jul 28.

  PMID: 28752258 BACKGROUND

• Kadauke S, Myers RM, Li Y, Aplenc R, Baniewicz D, Barrett DM, Barz Leahy A, Callahan C, Dolan JG, Fitzgerald JC, Gladney W, Lacey SF, Liu H, Maude SL, McGuire R, Motley LS, Teachey DT, Wertheim GB, Wray L, DiNofia AM, Grupp SA. Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial. J Clin Oncol. 2021 Mar 10;39(8):920-930. doi: 10.1200/JCO.20.02477. Epub 2021 Jan 8.

  PMID: 33417474 BACKGROUND

• Chiesa R, Wang J, Blok HJ, Hazelaar S, Neven B, Moshous D, Schulz A, Hoenig M, Hauck F, Al Seraihy A, Gozdzik J, Ljungman P, Lindemans CA, Fernandes JF, Kalwak K, Strahm B, Schanz U, Sedlacek P, Sykora KW, Aksoylar S, Locatelli F, Stepensky P, Wynn R, Lum SH, Zecca M, Porta F, Taskinen M, Gibson B, Matthes S, Karakukcu M, Hauri-Hohl M, Veys P, Gennery AR, Lucchini G, Felber M, Albert MH, Balashov D, Lankester A, Gungor T, Slatter MA. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. 2020 Sep 3;136(10):1201-1211. doi: 10.1182/blood.2020005590.

  PMID: 32614953 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Granulomatous Disease, Chronic

Interventions

Sirolimus; Cyclophosphamide; Alemtuzumab; Busulfan; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Radiotherapy; Therapeutics; Investigative Techniques

Study Officials

• Elizabeth M Kang, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sandra M Maxwell, R.N.

CONTACT

(240) 627-3078; maxwells@mail.nih.gov

Elizabeth M Kang, M.D.

CONTACT

(301) 402-7567; ekang@niaid.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2022
• First Posted: July 18, 2022
• Study Start: July 8, 2022
• Primary Completion (Estimated): December 31, 2032
• Study Completion (Estimated): December 31, 2032
• Last Updated: May 5, 2026

Record last verified: 2026-05-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Data availability and the duration of the data availability are as follows: Transplant data shared with the following groups will be shared at the onset of the signing of the protocol and will be maintained in shared data bases with no end date. (BTRIS), Neutrophil Monitoring Laboratory (NML), The NIH and other government agencies, like the Food and Drug Administration (FDA), which are involved in keeping research safe for people, NIH Intramural Institutional Review Board, The Center for Blood and Marrow Transplant Research, Study sponsor (NIAID), NHLBI s Data Safety and Monitoring Board, Blood and Inherited Disorder-Transplant and Cellular Therapy Program, Study monitors (NIAID/Office of Clinical Research Policy and Regulatory Operations NIAID/OCRPRO). Transplant data submitted for publication will be immediately available following publication with no end date.
• Access Criteria: Individual deidentified participant data will be shared with: A public repository, (CIBMTR), as required by the Stem Cell Act 2005 through the Forms Net database system. An NIH-funded or approved public repository. Publications, Public presentations, Individual identified participant data will be shared, approved outside collaborators under appropriate agreements, such as the NMLab in Md. Identified data in (BTRIS). The following data will be shared: All the individual participant data collected during the trial, after deidentification. The following related documents will be available: Study Protocol, Statistical analysis plan, Analytic code. Data and the duration of the data availability are as follows: Transplant data shared with CIBMTR, BTRIS, and the NML will be shared at the onset of signing the protocol and will be maintained in shared databases with no end date. Transplant data submitted for publication will be immediately available following publication with no end date.

Locations

US (1)