NCT01570348

Crohn's Allogeneic Transplant Study

Allogeneic Hematopoietic Cell Transplantation for Patients With Treatment-Refractory Crohn's Disease: A Phase 2 Study

• Status: Terminated
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 2 (actual)
• Sponsor: Fred Hutchinson Cancer Center · Academic / Other
• Sex: All
• Age: 18 Years – 60 Years
• Healthy volunteers: Not accepted

Summary

This phase II trial studies how well giving a donor bone marrow transplant (BMT) works in treating patients with refractory Crohn's Disease. We will select patients with severe Crohn's Disease and active inflammation despite the best medical and surgical treatments. These patients must be healthy enough to undergo a transplantation procedure. They cannot have an active infection, and their heart, lungs, kidneys, and liver cannot be failing. The transplant procedure starts with chemotherapy and a small dose of radiation, to weaken a patient's immune system so that it will accept bone marrow cells from another person. After that other person's bone marrow cells are given to the patient, immune suppressive medicines are given to prevent the new cells from being rejected and to stop those cells from damaging the patient. After the new donor cells start to work, blood counts will rise and the new immune system will start to grow. During this time, there is a risk of infection. Antibiotics and anti-viral drugs will be given to prevent infection. When the new donor cells are well-established, immune suppressive medicines are discontinued. We will examine parts of the intestine that were inflamed before the start of the transplant procedure, to be sure the Crohn's Disease has disappeared after the transplant. Patients will be formally evaluated for Crohn's activity at around 100 days after transplant, and yearly after that for 5 years.

Detailed description

BACKGROUND: There is strong evidence for genetic susceptibility to Crohn's Disease (CD), with environmental factors interacting with genetic polymorphisms. Some patients remain refractory to the best available therapies. In patients with intestinal inflammation related to other genetic disorders, allogeneic hematopoietic cell transplantation has led to disappearance of inflammation, for example, in patients with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) and with a mutation in the Interleukin-10 receptor, characterized by a severe, early onset, fistulating colitis for which transplantation is the only therapy that offers benefit. Eleven patients with typical CD who achieved allogeneic donor chimerism after transplant had resolution of signs and symptoms of CD that was sustained for up to 15 years. These case series suggest that allogeneic transplantation has substantial potential to cure CD. HYPOTHESIS AND SPECIFIC AIMS: The hypothesis is: Allogeneic hematopoietic cell transplantation (HCT) can achieve sustained remissions in patients with refractory CD, and can be done safely. The specific aims are: 1) To evaluate the safety and efficacy of allogeneic HCT as treatment for refractory CD. 2) To evaluate treatment effect on CD activity/severity using the Crohn's Disease Activity Index (CDAI) and the Simple Endoscopic Score for CD (SES-CD). 3) To evaluate safety by scoring regimen-related toxicities, time to engraftment, infectious complications, acute and chronic Graft-versus-Host Disease (GVHD), and treatment-related mortality. 4) To evaluate the effect on quality of life. METHODS: This study is a prospective single-arm Phase II clinical trial that will enroll 12 patients. PATIENT SELECTION: Patients will have documented CD (see eligibility criteria below); signs and symptoms that have failed to respond satisfactorily to medical and surgical therapies; active intestinal inflammation by endoscopy and histology, and CDAI \>= 250 or need for total parenteral nutrition or recurrent inflammation after resection. Donors will be a Human Leukocyte Antigen (HLA)-matched sibling or unrelated donor. ALLOGENEIC TRANSPLANT PROCEDURE: Patients will receive a reduced-intensity conditioning regimen of cyclophosphamide, fludarabine and low-dose Total Body Irradiation (TBI), a regimen that has been used successfully in patients receiving haploidentical allografts. Marrow will be used as the graft source to reduce the risk of GVHD. GVHD prophylaxis will consist of post-transplant high-dose cyclophosphamide followed by the combination of tacrolimus and enteric coated mycophenolic acid. Supportive care includes the use of N-acetyl cysteine infusions to reduce the risk of sinusoidal liver injury from cyclophosphamide; prophylaxis with ursodiol to prevent cholestatic liver disease; and antimicrobial drugs as prophylaxis and preemptive treatment for infections by bacteria, fungi, herpes viruses, and Pneumocystis jiroveci. Tissue and blood samples will be archived for future studies and evaluation of immune reconstitution at predefined intervals. EFFICACY AND SAFETY ENDPOINTS: Safety and efficacy will be based on clinical assessments, laboratory testing, and gastrointestinal endoscopy and histology at baseline, at day 100 post-transplant, and yearly for 5 years. The primary endpoint is event-free survival at 1 year, defined as alive and free of active CD by endoscopy and biopsy. Transplant-related mortality is death occurring at any time after start of allogeneic HCT. Disease activity will be evaluated using CDAI. Quality of Life will be measured using the Short Inflammatory Bowel Disease Questionnaire. RISKS AND POTENTIAL BENEFITS: The major risks include regimen-related toxicity, infections, graft rejection, and GVHD. Autologous stem cells will be reserved in case of graft rejection. Recent advances in transplant technique have substantially reduced the mortality risk. Balancing these risks is the potential for allogeneic transplant to effect sustained remissions and cures of CD. PRIMARY OBJECTIVES: I. The primary objective is to evaluate the safety and efficacy of HCT as treatment for refractory CD. SECONDARY OBJECTIVES: I. To evaluate treatment effect on CD activity and severity. II. To evaluate safety of allogeneic HCT as determined by regimen-related toxicities, infectious complications, acute and chronic GVHD, treatment-related mortality, overall total mortality, and time to engraftment. III. To evaluate the effect of allogeneic HCT on quality of life (QOL) in patients with severe refractory CD. OUTLINE: CONDITIONING THERAPY: Patients receive fludarabine phosphate intravenously (IV) over 30-60 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients undergo 200 cGy of TBI on day -1. TRANSPLANTATION: Patients undergo allogeneic BMT on day 0. IMMUNOSUPPRESSIVE THERAPY: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days 3-4, tacrolimus IV daily or orally (PO) twice daily (BID) on days 5-180 with taper to day 365, and mycophenolate acid enteric coated or mycophenolate mofetil PO three times daily (TID) on days 0-35. After completion of conditioning therapy and infusion of donor bone marrow cells, patients are followed up at 1 month, 3 months, 12 months, and then yearly thereafter for up to 60 months.

Conditions

• Crohn Disease

Interventions

Type	Name	Description
PROCEDURE	Allogeneic Bone Marrow Transplantation	Undergo allogeneic BMT
DRUG	Cyclophosphamide	Given IV
DRUG	Fludarabine Phosphate	Given IV
OTHER	Laboratory Biomarker Analysis	Correlative studies
DRUG	Mycophenolate Mofetil	Given PO
DRUG	Mycophenolic Acid	Given PO
OTHER	Quality-of-Life Assessment	Ancillary studies
DRUG	Tacrolimus	Given IV or PO
RADIATION	Total-Body Irradiation	Undergo TBI

Timeline

• Start date: 2012-07-17
• Primary completion: 2019-02-03
• Completion: 2019-10-30
• First posted: 2012-04-04
• Last updated: 2020-02-17
• Results posted: 2020-02-17

Locations

1 site across 1 country: United States