Non-myeloablative Haploidentical HCT Study for Patients With Sickle Cell Disease, Including Compromised Organ Function

NCT06145282 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: 10001635001635-H
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Sickle cell disease (SCD) is a genetic disorder where red blood cells, that carry oxygen, are stiff and become stuck in small blood vessels. As a result, affected patients can experience severe pain and serious organ damage. SCD can be cured with a hematopoietic cell transplant (HCT), that is, when they receive blood stem cells from a family donor. But HCT can also have serious side effects, especially in people with organ damage. Researchers want to find ways to make HCT safer for everyone. Objective: To test a new combination of drugs (briquilimab, abatacept, and alemtuzumab), used along with radiation, in people undergoing HCT for SCD. Eligibility: People aged 16 and older with SCD. They must be eligible for HCT and have a family member who is a good donor match. Donors must be aged 4 and older. Design: Participants with SCD will be screened. They will have blood tests and tests of organs including their heart and lung function. Donors will have blood drawn. Participants with SCD will have a tube inserted into a blood vessel in their chest (intravenously). This line will remain in place up to 2 months; it will be used to draw blood and administer the donor cells and other medications. Briquilimab will be administered intravenously 1 time, along with other drugs used to prepare for HCT. Participants will receive abatacept 6 times, from just before they receive their donor cells until 6 months after. Participants will undergo radiation therapy and take other drugs that are standard for HCT. Most HCT recipients remain in the hospital for about 30 days after HCT. Follow-up visits will continue for 5 years....

Conditions

Sickle Cell Disease

Keywords

Organ Damage; Hematopoietic Cell Transplant; Haploidentical; Sickle Cell Disease

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Successful Engraftment and Absence of Acute Grade 3 or Higher GVHD

  Number of participants at 1 year post stem cell transplant who have not experienced graft failure and who are without severe graft-versus-host disease (defined as grade 3 and higher acute GVHD). Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease. As defined by CIMBTR criteria for Organ Stages of Acute GVHD: Grade III: Skin = Rash on \>50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea \> 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin \>15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.

  Up to 1 year

• Number of Participants With Successful Engraftment and Absence of Moderate to Severe Chronic Graft-versus-host Disease

  Number of participants at 1 year post stem cell transplant who have not experienced graft failure and who are without moderate to severe chronic graft-versus-host disease (GVHD) Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease. CIMBTR criteria definition for Chronic GVHD: Moderate chronic GVHD involves EITHER 3 organs/sites with no clinically significant functional impairment OR a less than or equal to 1 organ/site with clinically significant functional impairment, but no major disability. Severe GVHD is associated with a major disability caused by chronic GVHD.

  Up to 1 year

Secondary Outcomes (3)

• Event-free Survival and Overall Survival

  length of study

• Viral Reactivation and Disease

  length of study

• Autoimmune and Hyperinflammatory Complications

  length of study

Study Arms (3)

PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

EXPERIMENTAL

Stem cell recipients with Sickle Cell Disease will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. This group will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT

Biological: Briquilimab; Drug: Abatacept; Drug: Sirolimus; Drug: Cyclophosphamide

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

EXPERIMENTAL

Stem cell recipients with Sickle Cell Disease will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. This group will receive a total of two doses of PT-Cy; 50mg/kg, on days +3 and +4 (total 100 mg/kg) post-HCT

Biological: Briquilimab; Drug: Abatacept; Drug: Sirolimus; Drug: Cyclophosphamide

Human Leukocyte Antigens (HLA) Haploidentical Related Stem Cell Donor

OTHER

A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).

Drug: Filgrastim

Interventions

Briquilimab BIOLOGICAL

All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy); PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

Filgrastim DRUG

A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).

Also known as: Granulocyte colony-stimulating factor (G-CSF)

Human Leukocyte Antigens (HLA) Haploidentical Related Stem Cell Donor

Abatacept DRUG

All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy); PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

Sirolimus DRUG

All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy); PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

Cyclophosphamide DRUG

For cohort 1, stem cell recipient participants will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT. For cohort 2, stem cell participants will receive two doses of PT-Cy; 50mg/kg, on days +3 and +4 (total 100 mg/kg) post-HCT.

Also known as: Cy

PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy); PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy)

Eligibility Criteria

• Age: 4 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient:
• Participants must fulfill one disease category, either at least one organ damage or no other access to curative therapy.
• Adult patients with sickle cell disease at high risk for disease-related morbidity or mortality, according to A, B, C, D, or E or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F):
• A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (\>=200 m/s); OR
• B. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR
• C. Sickle cell-related renal insufficiency defined by a creatinine level \>=1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome; OR
• D. Tricuspid regurgitant jet velocity (TRV) of \>=2.5 m/s at least 3 weeks after a vaso-occlusive crisis and/or right heart catheterization-documented pulmonary hypertension; OR
• E. Sickle hepatopathy defined as EITHER ferritin \>1000 mcg/L OR direct bilirubin \>0.4 mg/dL at baseline AND a platelet count \<250 K/microliter (without vaso-occlusive crisis); OR
• F. Any one of the below complications:
• Complication: Vaso-occlusive crises; Eligible for HCT: \>1 hospital admission per year while on a therapeutic dose of a SCD treatment/medication
• Complication: Acute chest syndrome (ACS); Eligible for HCT: Any ACS while on SCD treatment/medication
• Pediatric patients with sickle cell disease at high risk for disease-related morbidity or mortality, defined as A, B, C, D, E, or F
• A. A neurological event resulting in focal neurologic deficits that lasted \>= 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both; OR
• B. Abnormal transcranial Doppler (TCD) measurement with a timed average maximum mean velocity of at least 200 cm/sec in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used \> 185 cm/sec plus evidence of intracranial vasculopathy; OR
• C. Silent Cerebral Infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2-weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR

You may not qualify if:

• Recipient:
• An individual who meets any of the following criteria will be excluded from participation in this study:
• Available HLA-matched sibling donor
• ECOG performance status of 3 or more.
• DLCO \<35% predicted (corrected for hemoglobin).
• Baseline oxygen saturation of \<85% or PaO2 \<70 mmHg
• Left ventricular ejection fraction: \<35% estimated by ECHO
• Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. HCT candidates with pre-transplant respiratory viral infections will undergo careful clinical assessment with the help of our transplant infectious disease team for lower respiratory tract disease, which may include thorough physical examination, imaging, and/or bronchoalveolar lavage. In case of lower respiratory tract disease or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity, the transplant will be delayed until resolution.
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant.
• Pregnant or breastfeeding
• Donor specific anti-HLA antibodies (DSAs) \>=2000 Mean Fluorescence Intensity (MFI)
• Patients seronegative for EBV who have EBV seropositive donors

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Filgrastim; Granulocyte Colony-Stimulating Factor; Abatacept; Sirolimus; Cyclophosphamide

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Globulins; Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds

Limitations and Caveats

Due to premature withdrawal of the study drug by the drug company, the study was terminated early.

Results Point of Contact

• Title: Dr. Courtney Fitzhugh
• Organization: National Heart, Lung, and Blood Institute (NHLBI)

courtney.fitzhugh@nih.gov

301.402.6496

Study Officials

• Courtney F Joseph, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: November 22, 2023
• First Posted: November 24, 2023
• Study Start: December 28, 2023
• Primary Completion: October 27, 2025
• Study Completion (Estimated): November 26, 2027
• Last Updated: April 29, 2026
• Results First Posted: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)