Autologous Stem Cell Transplant for Refractory Crohn's Disease

Phase 2

Withdrawn

• Conditions: Crohn's Disease
• Interventions: Drug: mobilization of stem cells to prepare for Leukapheresis; Other: Leukapheresis- Collection of stem cells; Drug: Preparative regimen 4-6 weeks after Leukapheresis; Other: Stem Cell Transplant; Drug: Low-dose IL-2 administration

• Registration Number: NCT02676622
• Lead Sponsor: Nationwide Children's Hospital

Brief Summary

Crohn's disease is an 'auto-immune' disorder of the gut. In this condition the body's own immune system is fighting its gut and causing inflammation and other symptoms. Patients who are refractory (not responding) to the medications usually used to control Crohn's disease (medicines like steroids, azathioprine, methotrexate, cyclophosphamide and antibodies like Infliximab), may consider being part of this study.

In this study, the investigators plan to wipe out (ablate) the 'faulty immune system' with medicines (immune-ablation) and then give back the patients own stored stem cells (that have been collected before) - a procedure called autologous (self) stem cell transplant (ASCT). Once the new immune system regrows again from the stem cells, it is hoped that the 'faulty' immune cells do not return again and do not fight the gut leading to remission from symptoms of Crohn's disease. The aim of this treatment therefore, is to reset or re-program the immune system, so that it does not fight the patient's own body.

Currently, there are very few trials and experience with this procedure in children and young adults. There have been a few studies that have shown benefit of ASCT procedure in adult patients. In some patients, the benefit lasted for 1-5 years; but 1 in 5 (20%) participants were not taking their medications for the Crohn's disease even 5 years after ASCT. Other 80% needed medications again, but in most cases with better disease control.

In order to potentially improve the long term outcomes of ASCT, the investigators are adding another medication (in addition to those used in adult studies) called IL-2 (Aldesleukin), which will be given as an every-other-day injection under the skin (subcutaneous) at very low doses for 6 weeks after the ASCT and can be taken at home. Low dose IL-2 is known to increase a type of immune cell called T-regulatory cells (Tregs) that make immune cells less reactive to self. Study doctors believe that increased population of Tregs after ASCT may lead to a better control of Crohn's disease- higher percentage of cures or disease control for a longer period of time compared to the previous adult trials.

Therefore, the goals of this study are-

1. To see if ASCT can be used safely and can provide substantial benefit in young adults who have refractory Crohn's disease.

2. To see if addition of IL-2 after the ASCT is safe and effective.

Detailed Description

Crohn's Disease (CD) is an immunologically mediated chronic illness that has a relapsing and remitting course, most commonly presenting in the 2nd or 3rd decade and causing life long impairment of health and quality of life. Mainstay of clinical treatment for severe disease is combination of anti-inflammatory agents like 5-aminosalicyaltes and immunosuppressive medications like corticosteroids and newer anti-TNF antibodies like Infliximab. None of the drugs are, at present, curative and a relevant subset of patients are refractory to many of these pharmacologic approaches.

Immunoablative treatment followed by autologous stem cell rescue (Autologous HSCT) has been tried in this refractory group of patients with successful results. Autologous HSCT works in this auto-immune setting through the eradication of effector/memory T-cell clones due to a direct immuno-ablative effect of drugs used in the preparative regimen; by leading to an immune-reset- recovering clones of T- cells from the infused stem cells do not mount an auto-immune response and are tolerant to 'self' antigens and, by upregulation of T regulatory cells (Treg, CD4+CD25+FOXP3+ or CD8+ FOXP3+) via change in cytokine mileu during transplant. Increased population of Tregs restricts the activity of self reactive effector T-cells.

This pilot study is designed to gain on the success of previously published adult studies of autologous HSCT in refractory CD, with the aim to confirm the feasibility, safety and efficacy of HSCT and ultra low dose IL-2 when given post-HSCT in pediatric patients and young adults. IL-2 in very low doses has been shown to increase the proliferation of Treg lymphocytes and decrease inflammatory response. Hence, use of IL-2 post-transplant will result in significant and persistent increase in Treg population that may lead to more durable remissions after immunoablative therapy.

This pilot will focus on the 'safety' of this treatment in pediatric population.Since, this combination of immuno-ablative therapy followed by ultra low dose IL-2 has not been studied in children with CD, therefore transplant related mortality (TRM) and severe toxicity (\> grade 3 toxicity by NCI criteria) will be monitored for 100 days post-transplant in all the patients and stopping rules will be enforced in case of excessive toxicity or TRM (\>10%). Correlative studies will be performed at specific time points to assess the cytokine and inflammatory markers, immune-reconstitution and quantitative Treg cells; while clinical assessments will be done for 1 year post-HSCT for disease activity, steroid free remission period to evaluate the 'clinical efficacy' of this procedure.

The major aim of this pilot is to generate the preliminary safety and cytokine profile data to confirm the feasibility and benefit of autologous HSCT and IL-2 in children and young adults with refractory CD.

Study Timeline

• Study Start: 2013-04
• Primary Completion: 2013-04
• Study Completion: 2013-04
• Study First Submitted: 2013-04-21
• Study First Submitted QC: 2016-02-03
• Study First Posted: 2016-02-08
• Status Verified: 2017-02
• Last Update Submitted: 2017-02-02
• Last Update Posted: 2017-02-03

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Age ≥ 12 and < 30 years
• Confirmed diagnosis of Crohn's Disease -Pediatric Crohn's Disease Activity Index (PCDAI) >30 or Crohn's Disease Activity Index (CDAI) of >250 any time within 3 months prior to enrollment and any one of the following- i)Endoscopic evidence of active disease confirmed on histology within 3 months prior to enrollment, or ii) Clear evidence of active small bowel Crohn's disease on small bowel imaging within 3 months prior to enrollment.
• Refractory Crohn's Disease: Moderate to severe disease that has been unresponsive to current or prior therapy with mercaptopurine and/or azathioprine (thiopurines), methotrexate and anti-TNF therapy. Patients should have relapsing disease (i.e. > 1 exacerbation/year) or corticosteroid dependence despite current or prior thiopurines, methotrexate and anti-TNF maintenance therapy or clear demonstration of intolerance or toxicity to these drugs. Patients who fail induction therapy with corticosteroids and anti-TNF therapy, and are therefore not eligible to receive maintenance therapy with thiopurines or methotrexate will also be candidates for enrollment.
• Current active disease and problems not amenable to surgery or patient at risk for developing short bowel syndrome.
• Negative stool culture, C. difficile, and negative CMV pcr (in stool or colonic biopsy). Patients with CMV colitis will receive a trial of anti-viral treatment and only responders will be considered eligible for inclusion.
• Female patients of childbearing potential must have a documented negative serum pregnancy test within 2 weeks prior to starting the mobilization regimen.
• Patients with a prior ileostomy or colostomy may enter the study. For this group of patients', physician's global assesment will be used to assess clinical activity of CD, as Pediatric CDAI and CDAI scoring method may not be representative of disease activity.
• Patients with abscesses are eligible to enroll once the abscesses or any other significant infection has resolved.

Exclusion Criteria

• Pregnancy or unwillingness to use adequate contraception during the study- if a woman is of childbearing age.

• HIV infection. -Organ function criteria-

  1. Renal: creatinine clearance < 50 ml/min/1.73m2 (measured or estimated).
  2. Cardiac: left ventricular ejection fraction <30% by multigated radionuclide angiography (MUGA) or a shortening fraction of < 25% by cardiac echocardiogram.
  3. Pulmonary Function tests: DLCO < 30% or patient on oxygen.
  4. Hepatic: serum bilirubin > 3 mg%; AST and ALT > 3x ULN for the institutional lab.

• Uncontrolled Hypertension (using age based criteria) despite at least 2 anti-hypertensive agents.

-Active Infection or risk thereof-

1. Current abscess or significant active infection (see 6.2.9 above)

2. Perianal infection is not an exclusion criterion, provided there is drainage with or without placement of seton.

3. Abnormal chest x ray (CXR) consistent with active infection or neoplasm.

   • Severe diarrhea due to short small bowel; pateints believed to have < 700 mm of small bowel and diarrhea attributable to this will be excluded.
   • Patients with toxic megacolon, active bowel obstruction or intestinal perforation.
   • Lack of insurance payer approval.
   • Unable to collect minimum cell dose from Leukapheresis required for transplant. These patients will be excluded from receiving the preparative regimen.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Stem-cell mobilization and Leukapheresis	Low-dose IL-2 administration	Stem-cell mobilisation will be achieved using Cyclophosphamide (CY) 4g/m² (2g/m2 on 2 consecutive days) followed 5 days later by filgrastim (G-CSF) 10 mg/kg injection. This will be done daily until the day before the last day of leukapheresis. The PBSCs will be harvested usually between day +9 and +11 of completing CY. Leukapheresis will be performed to a target cell dose of 3-8 x106 CD34+ cells/kg Approximately 1 month later patients will undergo HSCT
Stem-cell mobilization and Leukapheresis	Stem Cell Transplant	Stem-cell mobilisation will be achieved using Cyclophosphamide (CY) 4g/m² (2g/m2 on 2 consecutive days) followed 5 days later by filgrastim (G-CSF) 10 mg/kg injection. This will be done daily until the day before the last day of leukapheresis. The PBSCs will be harvested usually between day +9 and +11 of completing CY. Leukapheresis will be performed to a target cell dose of 3-8 x106 CD34+ cells/kg Approximately 1 month later patients will undergo HSCT
Stem-cell mobilization and Leukapheresis	mobilization of stem cells to prepare for Leukapheresis	Stem-cell mobilisation will be achieved using Cyclophosphamide (CY) 4g/m² (2g/m2 on 2 consecutive days) followed 5 days later by filgrastim (G-CSF) 10 mg/kg injection. This will be done daily until the day before the last day of leukapheresis. The PBSCs will be harvested usually between day +9 and +11 of completing CY. Leukapheresis will be performed to a target cell dose of 3-8 x106 CD34+ cells/kg Approximately 1 month later patients will undergo HSCT
Stem-cell mobilization and Leukapheresis	Leukapheresis- Collection of stem cells	Stem-cell mobilisation will be achieved using Cyclophosphamide (CY) 4g/m² (2g/m2 on 2 consecutive days) followed 5 days later by filgrastim (G-CSF) 10 mg/kg injection. This will be done daily until the day before the last day of leukapheresis. The PBSCs will be harvested usually between day +9 and +11 of completing CY. Leukapheresis will be performed to a target cell dose of 3-8 x106 CD34+ cells/kg Approximately 1 month later patients will undergo HSCT
Stem-cell mobilization and Leukapheresis	Preparative regimen 4-6 weeks after Leukapheresis	Stem-cell mobilisation will be achieved using Cyclophosphamide (CY) 4g/m² (2g/m2 on 2 consecutive days) followed 5 days later by filgrastim (G-CSF) 10 mg/kg injection. This will be done daily until the day before the last day of leukapheresis. The PBSCs will be harvested usually between day +9 and +11 of completing CY. Leukapheresis will be performed to a target cell dose of 3-8 x106 CD34+ cells/kg Approximately 1 month later patients will undergo HSCT

Primary Outcome Measures

Name	Time	Method
The primary endpoint of the study is feasibility and safety of the autologous HSCT and low dose IL-2 post-HSCT, as evaluated by day +100 TRM (transplant related mortality) and incidence of severe toxicity.	1 year after transplant

Secondary Outcome Measures

Name	Time	Method
Secondary endpoints are evaluations of the effects of HSCT on clinical and laboratory manifestations of Crohn's Disease, i.e. frequency of and types of transplant related complications that were observed.	1 year after transplant	Incidence of Infections: CMV reactivation and disease, adenovirus infection, BK virus reactivation, EBV PTLD and invasive fungal infections will be estimated and documented.