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)

Overview

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.

Interventions

• Device 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
• Drug Prednisone/Methylprenisolone
  Administered as part of the HSCT conditioning regimen
• Drug Palifermin
  Administered as part of the HSCT conditioning regimen
• Drug ATG
  Administered as part of the HSCT conditioning regimen
• Drug Clofarabine
  Administered as part of the HSCT conditioning regimen
• Drug Melphalan
  Administered as part of the HSCT conditioning regimen
• Radiation Total Body Irradiation
  200 cGy, administered as part of the HSCT conditioning regimen
• Drug Rituximab
  Administered as part of the HSCT conditioning regimen

Primary outcome measures

• Number of patients with myeloid engraftment [Time frame: Day 42 post-HSCT]
• Number of patients with Grade III-IV acute graft vs host disease (GVHD) [Time frame: Day 90 and 180 post-HSCT]
• Number of patients in remission of Crohn disease (Calprotectin) [Time frame: 2 years post-HSCT]
• Number of patients in remission of Crohn disease (wPCDAI or CDAI) [Time frame: 2 years post-HSCT]

Secondary outcome measures (11)

• Number of patients who achieve normal immune function derived from donor cells [Time frame: 1 year post-HSCT]
• Number of patients who achieve full donor chimerism [Time frame: 1 year post-HSCT]
• Number of patients with healthy immune cell function [Time frame: 1 year post-HSCT]
• Number of patients who regain CD3 cells [Time frame: Day 90 and 180 post-HSCT]
• Number of patients who experience moderate and severe chronic GvHD [Time frame: 1 year post-HSCT]
• Number of patients who experience severe infections [Time frame: 1 year post-HSCT]
• Patient survival [Time frame: 2 and 5 years post-HSCT]
• Number of patients with response in Crohn disease activity - 50% CRP or higher [Time frame: 1 and 2 years post-HSCT]
• Number of patients with response in Crohn disease activity - wPCDAI/CDAI [Time frame: 1 year post-HSCT]
• Number of patients with endoscopic healing [Time frame: 2 years post-HSCT]
• Number of patients with sustained steroid-free remission [Time frame: 2 years post-HSCT]

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:

• 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:

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:

• 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).
• Pregnant or lactating females.
• Lack of patient/parent/guardian informed consent.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Lucile Packard Children's Hospital — Palo Alto

Publications

• 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: PMID 27302973
• 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 a PMID 28067908
• 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. PMID 32103191
• 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 Disea PMID 32084423
• 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. Fron PMID 29312354
• 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. PMID 26303102
• 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 PMID 27377901
• 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):22 PMID 35704481

Identifiers

NCT: NCT06986382 · 78920

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗