Stem Cell Transplantation in Crohn's Disease

NCT ID: NCT04224558

Last Updated: 2025-02-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-15
• Study Completion Date: 2026-09-30

Brief Summary

Unfortunately, some patients with Crohn's disease (CD) fail to respond to the best clinical treatments and some only experience temporary benefit. For severe Crohn's disease, there is an experimental treatment called "high dose immunoablation" followed by autologous hematopoietic stem cell transplantation (HSCT). This study removes over active lymphocytes (immunoablation) and replaces them using blood stem cells that have been taken from the patient's own body. The aim of the study is to reset or reprogram the patient's immune system to its state prior to diagnosis.

Detailed Description

The treatment of Crohn's disease has proven to be quite efficacious in the majority of patients with the timely use of combination therapies for remission induction (corticosteroids and/or biologics) and maintenance of disease control (immunosuppressives and/or biologics). However, a proportion of patients fail to achieve complete and long term disease control and often require multiple intestinal surgeries with a risk of developing short bowel syndrome. Lymphoablation followed by hematopoietic stem cell transplantation to rescue the immune system has been proposed as an alternative strategy to induce long term disease control in this high-risk population. It has been demonstrated that despite the potential toxicity and morbidity associated with the procedure, the benefit-risk ratio is favorable. Hence, the investigators propose to offer HSCT to selected CD patients and to study mechanisms of reducing T cell autoreactivity which will hopefully lead to more focused therapeutic approaches in the future.

This is an open-label, non-randomized, non-blinded, prospective study in therapeutic refractory Crohn's patients, failing conventional therapy.

The primary objective is to evaluate the safety and potential clinical benefit of lymphoablation followed by autologous HSCT rescue in therapy refractory CD. Death (transplant-related mortality, TRM) and severe toxicity (≥ grade 3 toxicity; NCI Toxicity Criteria version 4.0) within the first 6 months after HSCT will be monitored to meet this end-point.

SECONDARY OBJECTIVES

1. To evaluate the incidence of HSCT related complications, i.e. viral reactivations (CMV, Adenovirus, EBV, BK virus) or fungal infections.

2. To evaluate the impact of HSCT on quality of life and school productivity.

3. To elucidate the underlying mechanism involved in the observed benefit of HSCT on CD.

First, the safety will be evaluated by the amount of related adverse events. All adverse events will be recorded in a standardized way and their relationship to the study protocol will be assessed at various short and long term time points.

Second, to determine clinical benefit, the percentage of patients in sustained disease remission at 0, 2, 4, 6, 12 and 24 months post HSCT will be determined. Sustained disease remission is defined as a Crohn's Disease Activity Index (CDAI) < 150 without the use of corticosteroids. In addition, mucosal healing will be assessed during ileocolonoscopy at 6 and 12 months following HSCT using the CD endoscopic index (SES).

SECONDARY ENDPOINTS

• Change in Crohn's disease endoscopic index after 6 and 12 months.

Conditions

Crohn Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HSCT after mobilization and conditioning

Mobilization and leukopheresis allow for stem cell harvest. Then conditioning is provided prior to stem cell transplantation, followed by post-transplant conditioning.

Interventions include:

1. Stem cell mobilization

2. Leukopheresis

3. Preparative regimen

4. Peripheral blood stem cell infusion

5. Post-PBSC infusion conditioning

Group Type: EXPERIMENTAL

Mesna

Intervention Type: DRUG

Stem Cell Mobilization: Infused according to institutional guidelines;

Post-PBSC Infusion Conditioning: Mesna provided with Cytoxan according to institutional protocol.

Cyclophosphamide

Intervention Type: DRUG

Stem Cell Mobilization:

Cyclophosphamide (CY) infused intravenously over 1 hour: 50 mg/kg (25 mg/kg/day on 2 consecutive days)

Filgrastim

Intervention Type: DRUG

Stem Cell Mobilization: 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 leukapheresis;

Post-PBSC Infusion Conditioning: Filgrastim administered intravenously 5 mcg/kg IV starting day + 5, continue until ANC of >1000/μL

Apheresis catheter placement

Intervention Type: PROCEDURE

Subjects will require placement of an Apheresis catheter by Intervention Radiologists on the day of collection of stem cells.

Leukapheresis

Intervention Type: PROCEDURE

Leukapheresis will be performed on a continuous flow separator machine according to institutional guidelines to target 3-8 x 10\^6 CD34+ cells/kg body weight.

Fludarabine

Intervention Type: DRUG

Preparative/Conditioning Regime Fludarabine given as 30 mg/m2 per dose x 4 days, beginning on day -6.

Methylprednisolone

Intervention Type: DRUG

Preparative/Conditioning Regime r-ATG pre-medication according to institutional guidelines

Diphenhydramine

Intervention Type: DRUG

Preparative/Conditioning Regime r-ATG premedication according to institutional guidelines

Acetaminophen

Intervention Type: DRUG

Preparative/Conditioning Regime r-ATG premedication according to institutional guidlines

anti-thymocyte globulin (rabbit)

Intervention Type: DRUG

Preparative/Conditioning Regime r-ATG administered intravenously: 2.5 mg/kg/dose IV over 6 hours on specified days (day -6,-4,-2); ); total 3 doses=7.5 mg/kg.

lymphocyte immune globulin

Intervention Type: DRUG

Preparative/Conditioning Regime In patients who develop severe allergic reactions to rATG (Thymoglobulin), it may be substituted by horse ATG (hATG, ATGAM, Pharmacia \& Upjohn, Kalamazoo, MI). The recommended dose of hATG is 25 mg/kg/day for 3 doses.

Peripheral Blood Stem Cell Infusion

Intervention Type: BIOLOGICAL

PBSC (peripheral blood stem cell) infusion on day 0 as per institutional guidelines.

Cytoxan

Intervention Type: DRUG

Post-PBSC Infusion Conditioning Cytoxan infused intravenously: 50mg/kg/day x 2 days. Infused over 2 hours with adequate hydration or according to institutional guidelines.

Interventions

Mesna

Stem Cell Mobilization: Infused according to institutional guidelines;

Post-PBSC Infusion Conditioning: Mesna provided with Cytoxan according to institutional protocol.

Intervention Type: DRUG

Cyclophosphamide

Stem Cell Mobilization:

Cyclophosphamide (CY) infused intravenously over 1 hour: 50 mg/kg (25 mg/kg/day on 2 consecutive days)

Intervention Type: DRUG

Filgrastim

Stem Cell Mobilization: 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 leukapheresis;

Post-PBSC Infusion Conditioning: Filgrastim administered intravenously 5 mcg/kg IV starting day + 5, continue until ANC of >1000/μL

Intervention Type: DRUG

Apheresis catheter placement

Subjects will require placement of an Apheresis catheter by Intervention Radiologists on the day of collection of stem cells.

Intervention Type: PROCEDURE

Leukapheresis

Leukapheresis will be performed on a continuous flow separator machine according to institutional guidelines to target 3-8 x 10\^6 CD34+ cells/kg body weight.

Intervention Type: PROCEDURE

Fludarabine

Preparative/Conditioning Regime Fludarabine given as 30 mg/m2 per dose x 4 days, beginning on day -6.

Intervention Type: DRUG

Methylprednisolone

Preparative/Conditioning Regime r-ATG pre-medication according to institutional guidelines

Intervention Type: DRUG

Diphenhydramine

Preparative/Conditioning Regime r-ATG premedication according to institutional guidelines

Intervention Type: DRUG

Acetaminophen

Preparative/Conditioning Regime r-ATG premedication according to institutional guidlines

Intervention Type: DRUG

anti-thymocyte globulin (rabbit)

Preparative/Conditioning Regime r-ATG administered intravenously: 2.5 mg/kg/dose IV over 6 hours on specified days (day -6,-4,-2); ); total 3 doses=7.5 mg/kg.

Intervention Type: DRUG

lymphocyte immune globulin

Preparative/Conditioning Regime In patients who develop severe allergic reactions to rATG (Thymoglobulin), it may be substituted by horse ATG (hATG, ATGAM, Pharmacia \& Upjohn, Kalamazoo, MI). The recommended dose of hATG is 25 mg/kg/day for 3 doses.

Intervention Type: DRUG

Peripheral Blood Stem Cell Infusion

PBSC (peripheral blood stem cell) infusion on day 0 as per institutional guidelines.

Intervention Type: BIOLOGICAL

Cytoxan

Post-PBSC Infusion Conditioning Cytoxan infused intravenously: 50mg/kg/day x 2 days. Infused over 2 hours with adequate hydration or according to institutional guidelines.

Intervention Type: DRUG

Other Intervention Names

Mesnex; Cytoxan; Neosar; Neupogen; Granix; Fludara; solu-medrol; Benadryl; Tylenol; thymoglobulin; ATGAM; Cyclophosphamide

Eligibility Criteria

Inclusion Criteria

1. Aged 13-28 years are eligible

2. Confirmed diagnosis of active Crohn's disease:

1. Diagnosis of Crohn's disease based on typical radiological appearances and / or typical histology at least 6 months prior to screening.

2. Active disease at the time of registration to the trial, defined as

i) PCDAI > 30, and ii) Two of the following:

1. elevated CRP

2. endoscopic evidence of active disease confirmed by histology

3. clear evidence of active small bowel Crohn's disease on CT or MR enterography.

3. Unsatisfactory course despite 3 immunosuppressive agents (usually azathioprine, methotrexate and infliximab, adalimumab and/or certolizumab) in addition to corticosteroids. Patients should have relapsing disease (i.e. 1 exacerbation/year) despite thiopurines, methotrexate and/or infliximab/adalimumab/certolizumab maintenance therapy or clear demonstration of intolerance / toxicity to these drugs.

4. Current problems unsuitable for surgery or patient at risk for developing short bowel syndrome.

5. Accepted by a majority of the members of the combined IBD Center as an appropriate candidate (see Selection description below).

6. Informed consent

1. Prepared to undergo additional study procedures as per trial schedule

2. Patient has undergone intensive counseling about risks

Exclusion Criteria

1. Pregnancy or unwillingness to use adequate contraception during the study, in women of childbearing age. Unwillingness of using appropriate contraceptive measures in males.

2. Concomitant severe disease

1. renal: creatinine clearance < 30 mL/min (measured or estimated)

2. cardiac: clinical evidence of refractory congestive heart failure; left ventricular ejection fraction < 40% by cardiac echo; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consequences as evaluated by an experienced echo cardiographer

3. pulmonary: diffusion capacity <40%

4. psychiatric disorders including active drug or alcohol abuse

5. concurrent or recent history of malignant disease (excluding non-melanoma skin cancer)

6. uncontrolled hypertension, defined as resting systolic blood pressure ≥ 140 and/or resting diastolic pressure ≥ 90 despite at least 2 anti-hypertensive agents.

7. any infection with HIV, HTLV-1 or 2, hepatitis viruses, or any other infection the investigators consider a contraindication to participation.

8. other chronic disease causing significant organ failure.

3. Infection or risk thereof:

1. Current clinical relevant abscess or significant active infection.

2. Perianal fistula without free drainage. Perianal fistulas is not an exclusion provided there is natural free drainage or a seton suture(s) have been placed.

3. History of tuberculosis or at current increased risk of tuberculosis

4. Quantiferon Gold test result or other investigations that the investigators regard as evidence of active tuberculosis.

5. Abnormal chest X-ray (CXR) consistent with active infection or neoplasm.

6) Significant malnutrition: Body Mass Index (BMI) ≤ 18, serum albumin < 20 g/l.

7) Previous poor compliance. 8) Concurrent enrollment in any other protocol using an investigational drug or hematopoietic growth factor up to four weeks before study entry.

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 28 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cedars-Sinai Medical Center

OTHER

Sponsor Role: lead

Responsible Party

David Ziring

Associate Director, Pediatric IBD Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David Ziring, MD

Role: PRINCIPAL_INVESTIGATOR

Cedars-Sinai Medical Center

Locations

Cedars-Sinai Medical Center

Los Angeles, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

David Ziring, MD

Role: CONTACT

david.ziring@cshs.org

310-423-7100

Yvette Gonzales, MBA

Role: CONTACT

Yvette.Gonzales@cshs.org

310-423-4072

Facility Contacts

David Ziring, MD

Role: primary

David.Ziring@cshs.org

310-423-7100

Yvette Gonzales, MBA

Role: backup

Yvette.Gonzales@cshs.org

310-423-4072

Other Identifiers

Pro00051458

Identifier Type: -

Identifier Source: org_study_id