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
NCT ID: NCT06986382
Last Updated: 2025-05-23
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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NOT_YET_RECRUITING
PHASE1/PHASE2
14 participants
INTERVENTIONAL
2025-07-31
2040-07-31
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Cohort 1b: Safety Lead-In
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.
CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System
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.
Prednisone/Methylprenisolone
Administered as part of the HSCT conditioning regimen
Palifermin
Administered as part of the HSCT conditioning regimen
ATG
Administered as part of the HSCT conditioning regimen
Clofarabine
Administered as part of the HSCT conditioning regimen
Melphalan
Administered as part of the HSCT conditioning regimen
Total Body Irradiation
200 cGy, administered as part of the HSCT conditioning regimen
Rituximab
Administered as part of the HSCT conditioning regimen
Cohort 2a
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.
CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System
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.
Prednisone/Methylprenisolone
Administered as part of the HSCT conditioning regimen
Palifermin
Administered as part of the HSCT conditioning regimen
ATG
Administered as part of the HSCT conditioning regimen
Clofarabine
Administered as part of the HSCT conditioning regimen
Melphalan
Administered as part of the HSCT conditioning regimen
Total Body Irradiation
200 cGy, administered as part of the HSCT conditioning regimen
Rituximab
Administered as part of the HSCT conditioning regimen
Interventions
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CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System
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.
Prednisone/Methylprenisolone
Administered as part of the HSCT conditioning regimen
Palifermin
Administered as part of the HSCT conditioning regimen
ATG
Administered as part of the HSCT conditioning regimen
Clofarabine
Administered as part of the HSCT conditioning regimen
Melphalan
Administered as part of the HSCT conditioning regimen
Total Body Irradiation
200 cGy, administered as part of the HSCT conditioning regimen
Rituximab
Administered as part of the HSCT conditioning regimen
Other Intervention Names
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Eligibility Criteria
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Inclusion 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.
Exclusion Criteria
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.
2 Years
30 Years
ALL
No
Sponsors
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Stanford University
OTHER
Responsible Party
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Jessie L. Alexander
Principal Investigator
Principal Investigators
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Jessie Alexander, MD
Role: PRINCIPAL_INVESTIGATOR
Stanford University
Locations
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Lucile Packard Children's Hospital
Palo Alto, California, United States
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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78920
Identifier Type: -
Identifier Source: org_study_id
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