Phase 1b/2a Trial of Allogeneic HSCT From an HLA-partially Matched Related or Unrelated Donor After TCRab+ T-cell/CD19+ B-cell Depletion for Patients With Monogenic and/or Early-onset Medically Refractory Crohn Disease

Phase 1

Not yet recruiting

• Conditions: Crohn Disease
• Interventions: Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System; Drug: Prednisone/Methylprenisolone; Drug: Palifermin; Drug: ATG; Drug: Clofarabine; Drug: Melphalan; Radiation: Total Body Irradiation; Drug: Rituximab

• Registration Number: NCT06986382
• Lead Sponsor: Stanford University

Brief Summary

This research study is investigating whether alpha beta T-cell depleted hematopoietic stem cell transplant (HSCT) can be an immune system replacement for Crohn disease patients and whether this is safe and effective for patients with early onset, medically refractory Crohn disease.

Detailed Description

This is a single center, non-randomized, non-controlled open-label Phase 1b/2a trial to study the safety and efficacy of performing TCRαβ+ T-cell/CD19+ B-cell depleted (TCRαβ-depleted) HSCT to induce immune tolerance in patients with monogenic or early onset, medically refractory Crohn disease to re-establish normal immune-intestinal homeostasis.

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-20
• Study First Submitted QC: 2025-05-20
• Last Update Submitted: 2025-05-20
• Study First Posted: 2025-05-23
• Last Update Posted: 2025-05-23
• Study Start: 2025-07
• Primary Completion: 2037-07
• Study Completion: 2040-07

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

1. Meets at least one of the following criteria:

a. Known monogenic ("Mendelian") cause of IBD for which HSCT has been successfully performed i. Causative gene mutation known for which HSCT is demonstrated to be curative (e.g., IL10, IL10RA, IL10RB, XIAP, IPEX, WAS, CD40L, CGD, LRBA, CTLA4, DOCK8 and SCID syndromes).

b. Known monogenic cause of CD for which HSCT has not been previously performed i. Causative gene mutation expressed in lymphohematopoietic cells, for which HSCT has not been previously performed; AND ii. Moderate disease activity (shown through endoscopic, MRI, or PCDAI score); AND iii. Has been treated with at least two available treatment pathways (e.g., TNF inhibitors, anti-IL12 and /or IL-23 antibodies, JAK inhibitors, anti-integrin), but did not have adequate response, experienced significant toxicity, or had adverse effect(s) c. Suspected monogenic cause of CD i. Rare variant in a gene predicted to be functionally deleterious, suspected to drive IBD, and expressed in lymphohematopoietic cells; AND ii. Moderate disease activity or corticosteroid-dependence despite trials of at least two biologic or small molecule therapies of different mechanisms or significant toxicity or adverse effect related to such medical therapy.

d. Medically refractory CD with suspected strong genetic component, but no clearly identified deleterious single gene mutation.

i. Moderate or severe disease activity with either:

1. history of corticosteroid-dependence despite trials of at least two biologic or small molecule therapies of different mechanisms,
2. significant toxicity, or adverse effects related to such medical therapy;

AND at least one of the following criteria from ii or iii below:

ii. Severity unlikely to be tolerable long-term due to the presence of either:

1. Disease not amenable to surgical therapy without risk of short bowel syndrome or permanent ileostomy;

2. Requirement for long-term parenteral nutrition;

3. Intolerable extraintestinal symptoms (e.g., arthritis, dermatitis); iii. Presence of any of the following features associated with high genetic contribution to disease:

4. Parental consanguinity 2. Strong family history of IBD (present in first degree relatives) 3. Diagnosis earlier than 6 years of age 4. Extraintestinal manifestations 5. Family history of CD, IBD or autoimmune disease 2. Age >2 year and < 30 years. 3. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB1.

5. Lansky/Karnofsky score ≥50; the Karnofsky Scale will be used in subjects ≥ 16 years of age, and the Lansky Scale will be used for those < 16 years of age.

6. All subjects ≥ 18 years of age must be able to give informed consent, or adults lacking capacity to consent must have a legally authorized representative (LAR) available to provide consent. For subjects <18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age-appropriate discussion and written assent will be obtained for those > 7 years of age, when appropriate.

7. Female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression.

Recipient

Exclusion Criteria

1. Ulcerative colitis

2. CD and associated extraintestinal manifestations responsive to medical therapy without corticosteroid-dependence or significant toxicity or adverse effects

3. Known or suspected functionally deleterious mutation in a gene that meets either of the following expression criteria:

   1. Specifically expressed in epithelial or stromal cells, but not expressed in lymphohematopoietic cells (e.g., TTC7A)
   2. Expected to be more functionally deleterious in cell types other than lymphohematopoietic cells than in lymphohematopoietic cell types

4. Active hemophagocytic lymphohistiocytosis (HLH). Patients with a history of hemophagocytic lymphohistiocytosis (HLH) are eligible, if there is no current clinical, histological, or biochemical evidence of HLH activity.

5. Dysfunction of liver, defined as:

   1. ALT/AST > 5 times upper normal value, or direct bilirubin > 3 times upper normal value; or
   2. Cirrhosis with bridging fibrosis (grade F3 or greater) or sclerosing cholangitis

6. Severe cardiovascular disease (e.g. left ventricular ejection fraction < 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction.

7. Severe renal dysfunction defined as serum creatinine >1.5 X upper limit of normal (ULN) or 24-hour creatinine clearance <50 ml/min/m2

8. Human immunodeficiency virus (HIV)-infected patients or patients with evidence of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

9. Past exposure to therapeutic radiation.

10. Previous allogeneic HSCT. Patients who have received previous autologous HSCT are eligible.

11. Active malignancy and patients who have history of malignancies, unless disease free for at least 2 years, with the exception of nonmelanoma skin cancer or carcinoma in situ (e.g., bladder, breast).

12. Pregnant or lactating females.

13. Lack of patient/parent/guardian informed consent.

14. Any severe concurrent uncontrolled disease which, in the judgement of the investigator, would place the patient at increased risk during participation in the study, other than primary disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 1b: Safety Lead-In	CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	Prednisone/Methylprenisolone	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	Palifermin	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	ATG	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	Clofarabine	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	Melphalan	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	Total Body Irradiation	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 1b: Safety Lead-In	Rituximab	An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving a conditioning regimen.
Cohort 2a	CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	Prednisone/Methylprenisolone	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	Palifermin	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	ATG	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	Clofarabine	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	Melphalan	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	Total Body Irradiation	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.
Cohort 2a	Rituximab	If the intervention is determined to be safe and non-futile, the study will continue to enroll 10 more patients under Phase 2a following the same treatment as Phase 1b.

Primary Outcome Measures

Name	Time	Method
Number of patients with myeloid engraftment	Day 42 post-HSCT	Cumulative incidence of donor myeloid engraftment by Day +42 post-HSCT. Myeloid engraftment is defined as ANC of \> 0.5 x 109/L for three consecutive laboratory values obtained on different days. Date of myeloid engraftment is the first date of the three lab values taken.
Number of patients in remission of Crohn disease (Calprotectin)	2 years post-HSCT	Cumulative incidence of patient who achieve remission defined by fecal calprotectin values less than 250 mg/g
Number of patients in remission of Crohn disease (wPCDAI or CDAI)	2 years post-HSCT	Cumulative incidence of remission demonstrated by weighted Pediatric Crohn's Disease Activity Index (wPCDAI) \<12.5 or Crohn's Disease Activity Index (CDAI) of \<150 if adult
Number of patients with Grade III-IV acute graft vs host disease (GVHD)	Day 90 and 180 post-HSCT	Cumulative incidence of acute GvHD (graded as II-IV and III-IV using the Magic criteria); Cumulative incidence of acute GvHD (graded as II-IV and III-IV using the Magic criteria); Cumulative incidence of acute GvHD (graded as II-IV and III-IV using the Magic criteria); Cumulative incidence of acute GvHD (graded using the Magic criteria)

Secondary Outcome Measures

Name	Time	Method
Number of patients who achieve full donor chimerism	1 year post-HSCT	Cumulative incidence of patient chimerism defined as \>95% of donor cells as assessed by peripheral blood (total, CD15+, CD3+, CD56+, CD19+, and CD34+) chimerism by short tandem repeat (STR) or next generation sequencing (NGS) analysis
Number of patients with healthy immune cell function	1 year post-HSCT	Cumulative incidence of patients who have mitogen and antigen specific T-cell proliferation or cytokine release in response to in vitro stimulation
Number of patients who regain CD3 cells	Day 90 and 180 post-HSCT	CD3 cell count of \>200/ uL
Number of patients who experience moderate and severe chronic GvHD	1 year post-HSCT	Cumulative incidence of patients experiencing moderate or severe chronic GvHD by NIH Consensus Criteria for Organ scoring of cGVHD
Number of patients who experience severe infections	1 year post-HSCT	Cumulative incidence of patients experiencing Grade 3 or higher CTCAE infections after HSCT
Patient survival	2 and 5 years post-HSCT
Number of patients with response in Crohn disease activity - 50% CRP or higher	1 and 2 years post-HSCT	Cumulative incidence of patients who have a \<0.5 mg/dL reduction in C-reactive protein (CRP)
Number of patients with response in Crohn disease activity - wPCDAI/CDAI	1 year post-HSCT	Cumulative incidence of patients who achieve wPCDAI score reduced by 17.5 points from baseline if pediatric, CDAI reduced by at least 100 points from baseline if adult
Number of patients with endoscopic healing	2 years post-HSCT	Endoscopic healing defined as ≤1 SEMA score
Number of patients with sustained steroid-free remission	2 years post-HSCT	Cumulative incidence of patients who are able to discontinue steroids for 3 or more months
Number of patients who achieve normal immune function derived from donor cells	1 year post-HSCT	Cumulative incidence of patients with age-appropriate normalization of peripheral blood lymphocyte numbers including T, NK and B cells

Trial Locations

Locations (1)

Lucile Packard Children's Hospital; 🇺🇸 Palo Alto, California, United States