Autologous Stem Cell Transplant for Refractory Crohn's Disease

NCT02676622 | Withdrawn Phase 2 DMC

• 1 other identifier: IRB1100448
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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. 1.To see if ASCT can be used safely and can provide substantial benefit in young adults who have refractory Crohn's disease.
2. 2.To see if addition of IL-2 after the ASCT is safe and effective.

Conditions

Crohn's Disease

Keywords

Crohn's Disease; Autologous Hematopoietic Stem cell Transplant; Cyclophosphamide; IL-2; Aldesleukin; Proleukin; PCDAI

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• 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

Study Arms (1)

Stem-cell mobilization and Leukapheresis

EXPERIMENTAL

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

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

Interventions

mobilization of stem cells to prepare for Leukapheresis DRUG

Cyclophosphomide 2 g/m2 x 2 consecutive days. Filgrastim (G-csf) 10 mcg/kg SC will start 5 days after the last dose of CY and will end the day before the last leukapharesis.

Also known as: Cytoxan, G-csf, Neupogen

Stem-cell mobilization and Leukapheresis

Leukapheresis- Collection of stem cells OTHER

Placement of an Apheresis Catheter on the day of collection of stem cells. Leukapheresis will be performed on a continuous flow separator machine to target 3-8 x 106 CD34+ cells/kg body weight.

Also known as: white blood cells, Apheresis

Stem-cell mobilization and Leukapheresis

Preparative regimen 4-6 weeks after Leukapheresis DRUG

Prior to starting medicines, a central venous line will be placed (arm or chest) Cyclophosphamide iv: 50 mg/kg iv over 2 hours Mesna iv (uro-protectant): 36 mg/kg iv over 12 hours r-ATG (Thymoglobulin, Genzyme): 2.5 mg/kg/dose iv over 6 hours on days -3,-2,-1

Also known as: Cytoxan, Mesnex, Thymoglobulin, Genzyme

Stem-cell mobilization and Leukapheresis

Stem Cell Transplant OTHER

Infusion of the(cryopreserved and thawed)peripheral blood stem cells (PBSC)occurs on Day 0. Day +5: start Filgrastim (G-csf) subcutaneous injections Hospitalization in isolation room for 4-5 weeks

Also known as: HSCT, Neupogen

Stem-cell mobilization and Leukapheresis

Low-dose IL-2 administration DRUG

IL-2 Subcutaneous injections will start once ANC is \> 500/µL and patient is afebrile (start IL-2 will be approximately day +20)for 6 weeks of treatment. Once patient or parent has learnt the administration and patient is tolerating it well, then the rest of the treatment can be administered at home after discharge with weekly follow up visits.

Also known as: Aldesleukin

Stem-cell mobilization and Leukapheresis

Eligibility Criteria

• Age: 12 Years - 29 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• Pregnancy or unwillingness to use adequate contraception during the study- if a woman is of childbearing age.
• HIV infection. -Organ function criteria-
• Renal: creatinine clearance \< 50 ml/min/1.73m2 (measured or estimated).
• Cardiac: left ventricular ejection fraction \<30% by multigated radionuclide angiography (MUGA) or a shortening fraction of \< 25% by cardiac echocardiogram.
• Pulmonary Function tests: DLCO \< 30% or patient on oxygen.
• 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-
• Current abscess or significant active infection (see 6.2.9 above)
• 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.

Sponsors & Collaborators

• Nationwide Children's Hospital: lead

MeSH Terms

Conditions

Crohn Disease

Interventions

Leukapheresis; Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Filgrastim; Leukocyte Count; Blood Component Removal; Mesna; thymoglobulin; Stem Cell Transplantation; aldesleukin

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Cytapheresis; Biological Therapy; Therapeutics; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Blood Cell Count; Cell Count; Diagnostic Techniques and Procedures; Diagnosis; Hematologic Tests; Cell Physiological Phenomena; Blood Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Cell Transplantation; Cell- and Tissue-Based Therapy; Transplantation; Surgical Procedures, Operative

Study Officials

• Sandeep Soni, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2013
• First Posted: February 8, 2016
• Study Start: April 1, 2013
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: February 3, 2017

Record last verified: 2017-02