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

NCT06986382 | Not Yet Recruiting Phase 1 DMC FDA Device

• 1 other identifier: 78920
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Crohn Disease

Outcome Measures

Primary Outcomes (4)

• Number of patients with myeloid engraftment

  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.

  Day 42 post-HSCT

• Number of patients with Grade III-IV acute graft vs host disease (GVHD)

  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)

  Day 90 and 180 post-HSCT

• Number of patients in remission of Crohn disease (Calprotectin)

  Cumulative incidence of patient who achieve remission defined by fecal calprotectin values less than 250 mg/g

  2 years post-HSCT

• Number of patients in remission of Crohn disease (wPCDAI or CDAI)

  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

  2 years post-HSCT

Secondary Outcomes (11)

• Number of patients who achieve normal immune function derived from donor cells

  1 year post-HSCT

• Number of patients who achieve full donor chimerism

  1 year post-HSCT

• Number of patients with healthy immune cell function

  1 year post-HSCT

• Number of patients who regain CD3 cells

  Day 90 and 180 post-HSCT

• Number of patients who experience moderate and severe chronic GvHD

  1 year post-HSCT

Study Arms (2)

Cohort 1b: Safety Lead-In

EXPERIMENTAL

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.

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

Cohort 2a

EXPERIMENTAL

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.

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

Interventions

CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System DEVICE

CliniMACS® TCRαβ-Biotin and CD19 Systems will be used to create the mobilized peripheral blood stem cells (PBSC) from allogeneic donors depleted of TCRαβ+ T cells and CD19+ B cells to be infused into the patient for the HSCT. The target dose for the number of CD34+ HSC infused is \> 10 x 10\^6 cells/Kg recipient weight. The minimum dose is 2 x 10\^6 cells/Kg. There is no upper limit to the dose of CD34+ HSC infused as long as no more than 1 x 10\^5 TCRαβ+ T-cells/Kg are infused. The target dose of TCRαβ+ T cells/Kg is \< 0.50 x 10\^5.

Also known as: TCRαβ+ T-cells

Cohort 1b: Safety Lead-In; Cohort 2a

Prednisone/Methylprenisolone DRUG

Administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

Palifermin DRUG

Administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

ATG DRUG

Administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

Clofarabine DRUG

Administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

Melphalan DRUG

Administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

Total Body Irradiation RADIATION

200 cGy, administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

Rituximab DRUG

Administered as part of the HSCT conditioning regimen

Cohort 1b: Safety Lead-In; Cohort 2a

Eligibility Criteria

• Age: 2 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \. 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:
• history of corticosteroid-dependence despite trials of at least two biologic or small molecule therapies of different mechanisms,
• 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:
• Disease not amenable to surgical therapy without risk of short bowel syndrome or permanent ileostomy;
• Requirement for long-term parenteral nutrition;
• Intolerable extraintestinal symptoms (e.g., arthritis, dermatitis); iii. Presence of any of the following features associated with high genetic contribution to disease:
• \. 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.
• \. 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.
• \. 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.

You may not qualify if:

• Ulcerative colitis
• CD and associated extraintestinal manifestations responsive to medical therapy without corticosteroid-dependence or significant toxicity or adverse effects
• Known or suspected functionally deleterious mutation in a gene that meets either of the following expression criteria:
• Specifically expressed in epithelial or stromal cells, but not expressed in lymphohematopoietic cells (e.g., TTC7A)
• Expected to be more functionally deleterious in cell types other than lymphohematopoietic cells than in lymphohematopoietic cell types
• 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.
• Dysfunction of liver, defined as:
• ALT/AST \> 5 times upper normal value, or direct bilirubin \> 3 times upper normal value; or
• Cirrhosis with bridging fibrosis (grade F3 or greater) or sclerosing cholangitis
• Severe cardiovascular disease (e.g. left ventricular ejection fraction \< 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction.
• Severe renal dysfunction defined as serum creatinine \>1.5 X upper limit of normal (ULN) or 24-hour creatinine clearance \<50 ml/min/m2
• Human immunodeficiency virus (HIV)-infected patients or patients with evidence of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Past exposure to therapeutic radiation.
• Previous allogeneic HSCT. Patients who have received previous autologous HSCT are eligible.
• 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).

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Lucile Packard Children's Hospital

Palo Alto, California, 94305, United States

Location

Related Publications (13)

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• Stiff PJ, Leinonen M, Kullenberg T, Rudebeck M, de Chateau M, Spielberger R. Long-Term Safety Outcomes in Patients with Hematological Malignancies Undergoing Autologous Hematopoietic Stem Cell Transplantation Treated with Palifermin to Prevent Oral Mucositis. Biol Blood Marrow Transplant. 2016 Jan;22(1):164-9. doi: 10.1016/j.bbmt.2015.08.018. Epub 2015 Aug 22.

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MeSH Terms

Conditions

Crohn Disease

Interventions

Prednisone; Fibroblast Growth Factor 7; Clofarabine; Melphalan; Whole-Body Irradiation; Rituximab

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Fibroblast Growth Factors; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Radiotherapy; Therapeutics; Investigative Techniques; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins

Study Officials

• Jessie Alexander, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 20, 2025
• First Posted: May 23, 2025
• Study Start: July 1, 2025
• Primary Completion (Estimated): July 1, 2037
• Study Completion (Estimated): July 1, 2040
• Last Updated: May 23, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)