Clinical trial NCT06986382: 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
Official title: Phase 1b/2a Trial of Allogeneic Hematopoietic Stem Cell Transplantation (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 (EO), Medically Refractory (MR) Crohn Disease (CD)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Crohn Disease
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2025-05-23
Enrollment: 14
Sex: ALL
Minimum age (years): 2
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Recipient 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:

1. 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.

4. 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.

5. 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.

6. 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.

Primary outcomes:
measure: Number of patients with myeloid engraftment
timeFrame: Day 42 post-HSCT
measure: Number of patients with Grade III-IV acute graft vs host disease (GVHD)
timeFrame: Day 90 and 180 post-HSCT
measure: Number of patients in remission of Crohn disease (Calprotectin)
timeFrame: 2 years post-HSCT
measure: Number of patients in remission of Crohn disease (wPCDAI or CDAI)
timeFrame: 2 years post-HSCT
Secondary outcomes:
measure: Number of patients who achieve normal immune function derived from donor cells
timeFrame: 1 year post-HSCT
measure: Number of patients who achieve full donor chimerism
timeFrame: 1 year post-HSCT
measure: Number of patients with healthy immune cell function
timeFrame: 1 year post-HSCT
measure: Number of patients who regain CD3 cells
timeFrame: Day 90 and 180 post-HSCT
measure: Number of patients who experience moderate and severe chronic GvHD
timeFrame: 1 year post-HSCT
measure: Number of patients who experience severe infections
timeFrame: 1 year post-HSCT
measure: Patient survival
timeFrame: 2 and 5 years post-HSCT
measure: Number of patients with response in Crohn disease activity - 50% CRP or higher
timeFrame: 1 and 2 years post-HSCT
measure: Number of patients with response in Crohn disease activity - wPCDAI/CDAI
timeFrame: 1 year post-HSCT
measure: Number of patients with endoscopic healing
timeFrame: 2 years post-HSCT
measure: Number of patients with sustained steroid-free remission
timeFrame: 2 years post-HSCT
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
Study officials:
affiliation: Stanford University
name: Jessie Alexander, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kammermeier J, Dziubak R, Pescarin M, Drury S, Godwin H, Reeve K, Chadokufa S, Huggett B, Sider S, James C, Acton N, Cernat E, Gasparetto M, Noble-Jamieson G, Kiparissi F, Elawad M, Beales PL, Sebire NJ, Gilmour K, Uhlig HH, Bacchelli C, Shah N. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years. J Crohns Colitis. 2017 Jan;11(1):60-69. doi: 10.1093/ecco-jcc/jjw118. Epub 2016 Jun 14.
citation: de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, Kennedy NA, Jostins L, Rice DL, Gutierrez-Achury J, Ji SG, Heap G, Nimmo ER, Edwards C, Henderson P, Mowat C, Sanderson J, Satsangi J, Simmons A, Wilson DC, Tremelling M, Hart A, Mathew CG, Newman WG, Parkes M, Lees CW, Uhlig H, Hawkey C, Prescott NJ, Ahmad T, Mansfield JC, Anderson CA, Barrett JC. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
citation: Graham DB, Xavier RJ. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature. 2020 Feb;578(7796):527-539. doi: 10.1038/s41586-020-2025-2. Epub 2020 Feb 26.
citation: Crowley E, Warner N, Pan J, Khalouei S, Elkadri A, Fiedler K, Foong J, Turinsky AL, Bronte-Tinkew D, Zhang S, Hu J, Tian D, Li D, Horowitz J, Siddiqui I, Upton J, Roifman CM, Church PC, Wall DA, Ramani AK, Kotlarz D, Klein C, Uhlig H, Snapper SB, Gonzaga-Jauregui C, Paterson AD, McGovern DPB, Brudno M, Walters TD, Griffiths AM, Muise AM. Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center. Gastroenterology. 2020 Jun;158(8):2208-2220. doi: 10.1053/j.gastro.2020.02.023. Epub 2020 Feb 19.
citation: Cifaldi C, Chiriaco M, Di Matteo G, Di Cesare S, Alessia S, De Angelis P, Rea F, Angelino G, Pastore M, Ferradini V, Pagliara D, Cancrini C, Rossi P, Bertaina A, Finocchi A. Novel X-Linked Inhibitor of Apoptosis Mutation in Very Early-Onset Inflammatory Bowel Disease Child Successfully Treated with HLA-Haploidentical Hemapoietic Stem Cells Transplant after Removal of alphabeta+ T and B Cells. Front Immunol. 2017 Dec 22;8:1893. doi: 10.3389/fimmu.2017.01893. eCollection 2017.
citation: 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.
citation: Alatrash G, Thall PF, Valdez BC, Fox PS, Ning J, Garber HR, Janbey S, Worth LL, Popat U, Hosing C, Alousi AM, Kebriaei P, Shpall EJ, Jones RB, de Lima M, Rondon G, Chen J, Champlin RE, Andersson BS. Long-Term Outcomes after Treatment with Clofarabine +/- Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2016 Oct;22(10):1792-1800. doi: 10.1016/j.bbmt.2016.06.023. Epub 2016 Jul 1.
citation: Bertaina A, Grimm PC, Weinberg K, Parkman R, Kristovich KM, Barbarito G, Lippner E, Dhamdhere G, Ramachandran V, Spatz JM, Fathallah-Shaykh S, Atkinson TP, Al-Uzri A, Aubert G, van der Elst K, Green SG, Agarwal R, Slepicka PF, Shah AJ, Roncarolo MG, Gallo A, Concepcion W, Lewis DB. Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia. N Engl J Med. 2022 Jun 16;386(24):2295-2302. doi: 10.1056/NEJMoa2117028.
citation: Greco R, Labopin M, Badoglio M, Veys P, Furtado Silva JM, Abinun M, Gualandi F, Bornhauser M, Ciceri F, Saccardi R, Lankester A, Alexander T, Gennery AR, Bader P, Farge D, Snowden JA. Allogeneic HSCT for Autoimmune Diseases: A Retrospective Study From the EBMT ADWP, IEWP, and PDWP Working Parties. Front Immunol. 2019 Jul 4;10:1570. doi: 10.3389/fimmu.2019.01570. eCollection 2019.
citation: McLaughlin L, DeZoeten E, Verneris MR. Can allogeneic haematopoietic cell transplantation be curative in classical Crohn's disease? Br J Haematol. 2023 Mar;200(5):541-542. doi: 10.1111/bjh.18551. Epub 2022 Nov 9.
citation: Moser LM, Fekadu J, Willasch A, Rettinger E, Sorensen J, Jarisch A, Kirwil M, Lieb A, Holzinger D, Calaminus G, Bader P, Bakhtiar S. Treatment of inborn errors of immunity patients with inflammatory bowel disease phenotype by allogeneic stem cell transplantation. Br J Haematol. 2023 Mar;200(5):595-607. doi: 10.1111/bjh.18497. Epub 2022 Oct 10.
citation: Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, Shteyer E, Filiz S, Chee R, Elawad M, Hartmann B, Arkwright PD, Dvorak C, Klein C, Puck JM, Grimbacher B, Glocker EO. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013 Mar;131(3):825-30. doi: 10.1016/j.jaci.2012.09.025. Epub 2012 Nov 14.
citation: Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology. 1998 Mar;114(3):433-40. doi: 10.1016/s0016-5085(98)70525-6.