Pittsburgh, Pennsylvania 15224


Purpose:

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 young adult patients with severe Crohn's disease.


Study summary:

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.


Criteria:

Inclusion Criteria: - Patients who have experienced significant morbidity and reduced quality of life secondary to active CD are eligible. In general, CDAI should be >250 or PCDAI should be >30. - Patients should be between the ages 5 to 25 years. - Patients may be maintained on the optimal combination of medical therapy to stabilize their disease before the administration of high dose cyclophosphamide. - Hematopoietic: Platelet count greater than 100,000/mm3. Absolute neutrophil count greater than 1500/mm3 at initial evaluation (unless secondary to 6MP therapy). - Renal: Creatinine no greater than 2.0 mg/dL at initial evaluation. - Cardiovascular: No history of coronary artery disease: no congestive heart failure, resting LVEF at least 40% or shortening fraction at least 26% at initial evaluation. - Pulmonary: FEV1/FVC at least 60% predicted for age; DLCO at least 60% predicted value for age at initial evaluation. - Fertile patients must agree to use appropriate contraceptive measures. These patients will also be counseled regarding the potential risks of infertility following cyclophosphamide therapy. They will be advised to discuss sperm banking or egg harvesting from the ovary. - Patients must have available full-time caregiver for entire course of treatment with adequate social support. Exclusion Criteria: - Patients <5 years of age or >26 years of age. - Patients who have not been treated with adequate dosing of 6-MP, 5-aminosalicylate products and metronidazole. - Patients who sustained a decrement of 70 points on the CDAI or 15 points on the PCDAI, and maintain a CDAI < 250 and PCDAI < 30 after at least one 4 month course of prior anti-tumor necrosis factor alpha (infliximab). - Patient has localized area of Crohn's disease of intestine which is surgically correctable. - Patients with toxic megacolon, intestinal perforation - DLCO < 60% of normal value for age - Hepatic: Conjugated bilirubin greater than 2.0 mg/dL. Evidence of autoimmune chronic active hepatitis or sclerosing cholangitis - Patients with fever > 39o C or active infection within 1 week of stem cell mobilization and/or admission for conditioning regimen - Uncontrolled diabetes mellitus or other illness that would preclude study participation - Pregnancy or nursing mother - Massive splenomegaly - Presence of increased anesthetic risk if central line will be inserted or other procedure is expected to be performed under anesthesia. - HIV/HTLV seropositive, Hep B surface antigen positive, or HCV RNA positive by PCR


NCT ID:

NCT00692939


Primary Contact:

Principal Investigator
Paul Szabolcs, MD
Children's Hospital of Pittsburgh of UPMC

Paul Szabolcs, M.D.
Phone: 412-692-6225
Email: Paul.Szabolcs@chp.edu


Backup Contact:

Email: jason.rowan@chp.edu
Jason Rowan, RN
Phone: 412-692-6195


Location Contact:

Pittsburgh, Pennsylvania 15224
United States

Jason Rowan, RN
Phone: 412-692-6195
Email: jason.rowan@chp.edu

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: January 18, 2018

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