Autologous Stem Cell Transplantation for Crohn's Disease

Autologous Stem Cell Transplantation With CD34-Selected Peripheral Blood Stem Cells (PBSC) in Pediatric and Adult Patients With Severe Crohn's Disease

The objective of this study is to evaluate the safety and effectiveness of administering high-dose chemotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC) in pediatric and adult patients with severe Crohn's disease.

Study Overview

• Status: Recruiting
• Conditions: Crohn's Disease
• Intervention / Treatment: Biological: autologous CD34-selected peripheral blood stem cells transplant; Drug: Alemtuzumab; Drug: ATG; Drug: Melphalan; Drug: Thiotepa; Drug: Rituximab; Drug: Cyclophosphamide; Drug: G-CSF; Drug: Mesna

Detailed Description

Crohn's disease is considered to be an immune-mediated disease of the intestinal tract, typically treated using immune modulating or immune suppressive therapies. These treatments include local anti-inflammatory agents such as 5 aminosalicylic acid products, broad immune suppression using corticosteroids, azathioprine, or methotrexate; cytokine suppression such as antibody against TNFα; IL-12 and antibiotics such as ciprofloxacin and metronidazole that work by decreasing the putative antigen exposure to the intestine. There is little in the literature available on mortality data related to Crohn's Disease, but one series by Farmer et al showed 6% mortality attributable to Crohn's disease. The mortality rate for selective patients with refractory and severe disease is probably higher.

This protocol is based on the premise that the sustained inflammation of the GI tract that is characteristic of Crohn's disease is the result of defective mucosal T cell tolerance. The mucosal tolerance is normally maintained by CD4 + T cells characterized as T helper 3 (Th3) and T regulatory 1 (TR1) T cell clones producing TGFβ and IL-10 respectively. There has been much speculation on a possible infectious etiology of IBD implicating primarily mycobacterial organisms, though despite extensive research no pathogenic organisms have definitively been identified. In genetic cytokine knockout animal models of IBD, the typical nonpathogenic enteric flora is sufficient to induce a chronic inflammatory reaction. Autoreactive T cells appear to have broken through the mucosal tolerance with characteristic T helper 1 cytokine profile secreting IL-1 and IFNγ.

In theory the most efficient approach to eradicate autoimmune T cell clones is through replacement of the defective immune system with hematopoietic stem cells (HSC) from a healthy allogeneic donor. However, the risks of morbidity and mortality associated with allogeneic HSC transplantation currently do not appear to be justified even in treatment of refractory cases of Crohn's disease. An alternative approach is to use autologous HSC from which potential autoreactive T-cells have been eliminated, based on the hypothesis that from the T-cell depleted autologous graft reconstitution of normal immunity will occur without regeneration of autoimmune clones. Pilot trials in Crohn's and other autoimmune diseases have confirmed the validity of this hypothesis. T-cells in the CD34 selected PBSC product are significantly depleted. If active disease recurs despite intensive immunoablation, it is likely that either CD34 selection did not adequately remove cells responsible for the autoreactive state, or that the emerging genetically predisposed immune system was re-exposed to autoantigens.

Unlike allogeneic transplants, the autologous transplant approach has greatly reduced morbidity and mortality due to the absence of graft rejection and graft versus host disease reactions. Currently, autologous HSCT demonstrate that transplant-related mortality is around 5% when transplanted for acute leukemia.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Shawna H McIntyre, RN; Phone Number: 4126925552 412-692-5552; Email: mcintyresm@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC Prebyterian- Adult Gastroenterology
      • Contact: David Binion, MD; Phone Number: 412-383-6968; Email: binion@pitt.edu
      • Contact: Beata Pasek, RN; Phone Number: 412-648-6995; Email: BBP10@pitt.edu
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC-Bone Marrow Team
      • Principal Investigator: Paul Szabolcs, MD
      • Contact: Shawna H McIntyre, RN; Phone Number: 412-692-5552; Email: mcintyresm@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

5.1 Inclusion Criteria

1. Subject and/or guardian must be able to understand and provide informed consent.
2. Male or female, 10 through 60 years old, inclusive at time of informed consent.

3. Examples of subjects for whom stem cell transplant therapy would be appropriate include, but are not limited to:

   • Patients who have had prior surgery and subsequent severe recurrent disease in spite of aggressive maintenance therapy, necessitating consideration of further extensive surgical resections.
   • Patients who have diffuse small bowel and colonic disease and who are refractory to aggressive medical treatment, and not eligible for treatment using a surgical approach without the risk of precipitating short bowel syndrome and dependence of parenteral nutrition or who have other conditions that preclude surgery
   • Patients with a persistently high Harvey Bradshaw Index (HBI) (>6), CDAI (>250) or Pediatric CD Activity Index (PCDAI>45) (44) score or those in the lower, moderate range (HBI ≤ 6), (CDAI < 250), (PCDAI 30-45), but who are dependent on daily doses of corticosteroids, that are unable to be withdrawn, and aggressive medical treatment to maintain moderate disease status.
   • Patients who have resistant complications of CD unresponsive to medical management including multiple enteric fistulas, enterovesicular or enterovaginal fistulas, severe perianal disease, debilitating arthritis, severe skin lesions (pyoderma), and severe bony complications of the disease and therapy (aseptic necrosis, pathologic fractures).
   • Patients who developed severe complications to while receiving medical management such as pancreatitis following 6-Mercaptopurine, colitis following 5-ASA or those with severe hypersensitivity to TNFalpha inhibitors (infliximab, adalimumab, certolizumab pegol), anti-integrin agents (natalizumab, vedolizumab) or anti-IL12/23 agents (ustekinumab).
   • Patients with stomas are eligible.
4. No surgical therapeutic option secondary to risk of short bowel syndrome or patient refusal.
5. Harvey Bradshaw Index (HBI) or CD activity score >5, CDAI >250 or PCDAI >30.
6. Platelet count greater than 100,000/mm3.
7. Absolute neutrophil count greater than 1500/mm3 (unless secondary to 6MP therapy).
8. Creatinine ≤ 2.0 mg/dL.
9. No history of coronary artery disease; resting LVEF ≥ 40% or shortening fraction ≥ 26%.
10. FEV1/FVC ≥ 60% predicted for age; DLCO ≥ 60% predicted value for age.
11. Negative pregnancy test for females ≥ 10 years old or who have reached menarche, unless surgically sterilized.
12. All females or childbearing potential and sexually active males must agree to use a FDA approved method of birth control for up to 24 months after PBSC transplant or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.

5.2 Exclusion Criteria

1. Patients who have not been treated with adequate dosing of 6-MP, 5-ASA products and metronidazole.
2. Patients who achieved a sustained, corticosteroid free response to anti-TNF alpha therapy, anti-integrin therapy or anti-IL12/23 therapy after a 4 month course of treatment.
3. Toxic megacolon, intestinal perforation
4. Conjugated bilirubin > 2.0 mg/dL.
5. Pregnancy or nursing mother
6. HIV/HTLV seropositive, HBsAg, or HCV RNA positive by PCR
7. Active infection, as determined by the appropriate confirmatory testing e.g. blood cultures, PCR testing, etc., within two weeks of mobilization and high dose chemotherapy.
8. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 1; High-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC)

Biological: autologous CD34-selected peripheral blood stem cells transplant; high-dose immunotherapy followed by infusion of autologous CD34-selected peripheral blood stem cells (PBSC); Drug: Alemtuzumab; Transplant conditioning; Other Names: Campath-1H; Drug: ATG; Transplant conditioning; Other Names: Anti-thymocyte globulin, rabbit; Thymoglobulin; Drug: Melphalan; Transplant conditioning; Other Names: L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin; Drug: Thiotepa; Transplant conditioning; Drug: Rituximab; Transplant conditioning; Other Names: Rituxan; Drug: Cyclophosphamide; Mobilization; Other Names: Cytoxan; Drug: G-CSF; Mobilization; Other Names: Neupogen, Granix, Zarxio, Filgrastim; Drug: Mesna; Mobilization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants with regimen-related toxicities.	From baseline to 24 months post bone marrow transplant
Number of participants with life-threatening infections.	From baseline to 24 months post bone marrow transplant
Change and duration in the Harvey Bradshaw Index (HBI).	Change from Baseline to 24 months post Bone Marrow Transplant
Change and duration in the Crohn's Disease Activity Index (CDAI).	Change from Baseline to 24 months post Bone Marrow Transplant
Change and duration in the Pediatric Crohn's Disease Activity Index (PCDAI).	Change from Baseline to 24 months post Bone Marrow Transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of days it takes for Absolute Neutrophil Count (ANC) to reach greater than 500.	3 consecutive days once ANC is greater than 500.
Number of days it takes for Platelet count to reach greater than 20,000/mm3	From baseline to 24 months post Bone Marrow Transplant.
Number of days it takes for T cell Recovery	24 months post Bone Marrow Transplant
Number of participants who have long term cardiac complications	24 months post Bone Marrow Transplant
Number of participants who have long term endocrine complications	24 months post Bone Marrow Transplant
Number of participants with active advanced Crohn's disease who have immune dysregulation evolution and correction.	From Baseline to 24 months post bone marrow transplant
Biomarker identification for relapse	From baseline to 24 months post bone marrow transplant

Collaborators and Investigators

• Sponsor: Paul Szabolcs
• Investigators: Principal Investigator: Paul Szabolcs, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2012
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: June 3, 2008
• First Submitted That Met QC Criteria: June 5, 2008
• First Posted (Estimated): June 6, 2008

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Crohn's Disease; Stem cell transplantation
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Rituximab; Melphalan; Thiotepa; Thymoglobulin; Antilymphocyte Serum; Alemtuzumab
• Other Study ID Numbers: STUDY19100005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No