Crohn's Allogeneic Transplant Study (CATS)
Drug: fludarabine phosphate
Radiation: total-body irradiation
Procedure: allogeneic bone marrow transplantation
Drug: mycophenolic acid
Drug: mycophenolate mofetil
Other: quality-of-life assessment
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Allogeneic Hematopoietic Cell Transplantation for Patients With Treatment-Refractory Crohn's Disease: A Phase 2 Study|
- Event-free survival (EFS) [ Time Frame: At 1 year post-transplant ] [ Designated as safety issue: No ]Defined as alive and free of active CD. Described graphically using a Kaplan-Meier estimate. Generated with confidence intervals using Greenwood's formula to calculate the standard error. Estimated with exact 90% confidence intervals.
- EFS [ Time Frame: Up to 5 years post-transplant ] [ Designated as safety issue: No ]Described graphically using a Kaplan-Meier estimate. Generated with confidence intervals using Greenwood's formula to calculate the standard error. Estimated with exact 90% confidence intervals.
- Overall survival [ Time Frame: Time of treatment assignment until death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]Characterized by the event rates as functions of all patients enrolled and at risk of the event, with exact confidence intervals.
- Treatment-related mortality (TRM) [ Time Frame: Time from BMT to death definitely or probably resulting from treatment, assessed up to 5 years ] [ Designated as safety issue: No ]A stopping rule will be imposed for TRM occurring within one year of transplant. The study will be stopped if at any point there is moderately strong evidence that the rate of TRM exceeds 10%. Moderately strong evidence will be taken to mean that the lower bound of a one-sided 80% confidence interval for the true rate of TRM is above 10%.
- Regimen-related toxicity graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4 [ Time Frame: Up to 1 year post-BMT ] [ Designated as safety issue: Yes ]Characterized by the rates of reportable events as functions of all patients enrolled and at risk of the event, with exact confidence intervals. With the exception of adverse events (AEs) that are universal and expected following conditioning therapy, all reportable AEs will be tabulated for each patient from the time that the subject starts mobilization of hematopoietic cells until day +365 after transplant.
- Development of infectious complications [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient.
- Quality of life measured using the previously validated Short Inflammatory Bowel Disease Questionnaire [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
- Disease activity [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Evaluated using a standardized tool for evaluating CD (CDAI).
- Incidence of graft rejection [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Engraftment is defined as achieving > 5% donor peripheral blood CD3 T cell chimerism by day 84 after HCT. Primary graft failure is defined as a donor peripheral blood CD3 T cell chimerism peak of < 5% by Day 84 post-HCT. Secondary graft failure is defined as documented engraftment followed by loss of the graft with donor peripheral blood CD3 T cell chimerism < 5% as demonstrated by a chimerism assay.
- Incidence and severity of GVHD [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]The grading of acute and chronic GVHD will follow previously published guidelines but will also include capture of symptoms and characterization of alternative causes. The highest level of organ abnormalities, the etiologies contributing to the abnormalities and biopsy results pertaining to GVHD will be identified. Since both GVHD and CD involve the gastrointestinal tract, all diagnostic biopsies of these organs will be reviewed by pathologists experienced in the diagnosis of GVHD and IBD, respectively.
- Incidence of disease-modifying drugs for CD initiated post-transplant [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Includes the administration of any therapy (drugs, biologics, or any other treatments) clearly given as immunomodulatory therapy for underlying CD.
|Study Start Date:||July 2012|
|Estimated Primary Completion Date:||July 2017 (Final data collection date for primary outcome measure)|
Experimental: Treatment (allogeneic BMT)
CONDITIONING THERAPY: Patients receive fludarabine phosphate IV over 30-60 minutes QD on days -6 to -2 and cyclophosphamide IV over 1-2 hours QD on days -6 and -5. Patients undergo total body irradiation on day -1.
TRANSPLANTATION: Patients undergo donor BMT on day 0.
IMMUNOSUPPRESSIVE THERAPY: Patients receive high-dose cyclophosphamide IV over 1-2 hours QD on days 3-4, tacrolimus IV daily or PO BID on days 5-180 with taper to day 365, and mycophenolate acid enteric coated or mycophenolate mofetil PO TID on days 0-35.
Drug: fludarabine phosphate
Other Names:Drug: cyclophosphamide
Other Names:Radiation: total-body irradiation
Other Name: TBIProcedure: allogeneic bone marrow transplantation
Undergo allogeneic BMT
Other Names:Drug: tacrolimus
Given IV or PO
Other Names:Drug: mycophenolic acid
Other Names:Drug: mycophenolate mofetil
Other Names:Other: quality-of-life assessment
Other Name: quality of life assessmentOther: laboratory biomarker analysis
Hide Detailed Description
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.
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.
I. The primary objective is to evaluate the safety and efficacy of HCT as treatment for refractory CD.
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01570348
|United States, Washington|
|Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium|
|Seattle, Washington, United States, 98109|
|Principal Investigator:||George McDonald||Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium|