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Phase 2
18 Years
60 Years
Open (Enrolling)
Crohn Disease

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Trial Information



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.


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 an 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 Crohn's disease (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 total body irradiation 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 continuously or orally twice daily on days 5-180 with taper to day
365, and mycophenolate acid enteric coated or mycophenolate mofetil orally three times daily
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

Inclusion Criteria:

- The patients that will be eligible for enrollment on this study are individuals with
severe, treatment-refractory Crohn's Disease.

- A diagnosis of CD established by referring physician(s) and confirmed by our review
of the clinical presentation, clinical course, endoscopic and imaging findings, and
histology of mucosal tissue specimens.

- An adverse prognosis, documented by persistent signs and symptoms of CD that have
failed to respond satisfactorily to medical and surgical therapies in the past,
including but not limited to systemic immune suppressive drugs and
biopharmaceuticals; patients should have relapsing inflammatory mucosal disease
despite medications or clear demonstration of intolerance / toxicity to these drugs
and biopharmaceuticals; to be considered as refractory to medical and surgical
therapy, there must be clinical, endoscopic, and histologic evidence of active
inflammatory Crohn's Disease that has either persisted or recurred despite exhaustive
treatment with available pharmaceutical and surgical therapies; exhaustive treatment
is defined as prior exposure to the following, without durable improvement:

- Systemic glucocorticoids

- Methotrexate and/or a thiopurine antimetabolite. If a patient is homozygous
mutant for the TPMT gene, thiopurines would be contraindicated and their use
would not be a requirement for enrollment in this protocol

- Use of at least two anti-TNF-alpha therapies (infliximab and/or adalimumab
and/or certolizumab pegol)

- Exhaustive surgical treatment will be defined as indicated operations for
complications of Crohn's Disease up to the point where the risks of surgery are
deemed by patients and their physicians to be unacceptably high; indicated
operations for complications of Crohn's Disease include, but are not limited to,
surgical resection of involved intestine, stricturoplasty, drainage, curettage,
or adhesiolysis of tissues affected by Crohn's disease

- Exposure of patients to investigational drug therapies for Crohn's Disease, that
is, to drugs that are not FDA approved for this indication, will not be a
criterion for either inclusion or exclusion

- In the event that the involved mucosa cannot be readily reached by endoscopic biopsy,
an imaging test that shows typical changes of CD in the intestinal tract will suffice
as evidence of active intestinal inflammation; the presence of intestinal stomas does
not exclude the patient from study

- Severe CD as defined by one of the following:

- a. CDAI >= 250

- b. Need for total parenteral nutrition to maintain weight

- c. Recurrent intestinal inflammation caused by CD following surgical resection

- Identification of an HLA-matched hematopoietic cell donor without a history of a
disorder that can be transmitted by hematopoietic cells, including but not limited to
inflammatory bowel disease

- Age from 18 through 60 years

- DONORS will be an HLA-identical sibling or HLA-matched unrelated donor. Unrelated
donors are required to be matched by high resolution allele level typing for HLA-A,
B, C and DRB1 and intermediate resolution Sequence Specific Oligonucleotide Probes
(SSOP), identifying alleles in groups of related families historically defined as
antigens for DQB1. An unrelated donor is considered matched if patient and donor
share HLA-A, B, C alleles with identical sequences at exons 2 and 3, DRB1 alleles
with identical sequences at exon 2, and DQB1 results that include the same allele

- DONORS will have the ability to understand and the willingness to sign a written
informed consent document for bone marrow harvest.

Exclusion Criteria:

- Diagnosis of CD in a patient with an underlying immune deficiency disorder, including
but not limited to severe combined immunodeficiency (SCID), immunodysregulation
polyendocrinopathy enteropathy X-linked syndrome (IPEX), and others

- A current complication of CD that would jeopardize survival after hematopoietic cell
transplantation, including but not limited to the following:

- Abscess, phlegmon, necrotizing skin lesion, or inflammatory fistula

- Intestinal fibrotic stricture and intestinal obstruction

- Uncontrolled mucosal, organ, or systemic infection with a bacterial, viral,
fungal, or parasitic organism

- Sclerosing cholangitis

- History of progressive multifocal leukoencephalopathy

- Organ dysfunction or disease that would jeopardize survival after hematopoietic cell
transplantation, including but not limited to the following:

- Renal insufficiency as defined by an estimated Glomerular Filtration Rate (GFR)
< 60 mL/minute

- Cardiac dysfunction as defined by symptomatic coronary artery disease,
congestive heart failure, valvular heart disease, cardiomyopathy, uncontrolled
arrhythmia(s), or left ventricular ejection fraction < 50%

- Pulmonary dysfunction that poses a risk of mortality after transplant

- Necroinflammatory or fibrotic liver disease with evidence of liver dysfunction,
including but not limited to jaundice, hepatic encephalopathy, or portal

- Marrow dysfunction that poses a risk of peri-transplant mortality

- Poorly controlled hypertension despite appropriate therapy

- Neurologic dysfunction that affects activities of daily living and medical care

- Poorly controlled diabetes mellitus

- Extreme protein-calorie malnutrition defined by Body Mass Index < 18 kg/m^2 and
unintentional weight loss (3 kg in the last month or 6 kg in the last 6 months

- Pregnancy

- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following transplant

- History of smoking either tobacco or other herbal products in the last 6 months

- Human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis B virus

- Patients whose life expectancy is severely limited by illness other than CD

- Untreated psychiatric illness, including drug/alcohol abuse, that would compromise

- Inability to give voluntary informed consent or obtain a parent or guardian's
informed consent

- Demonstrated lack of compliance with prior medical care

- History of a malignancy, excluding adequately treated squamous cell skin cancer,
basal cell carcinoma, and carcinoma in situ

- Hematopoietic cell transplant-co-morbidity Index greater than 2 for adult patients

- DONOR: Identical twin

- DONOR: Pregnant or lactating females

- DONOR: HIV seropositivity or presence of HBV DNA or HCV RNA in the serum

- DONOR: Current serious systemic illness including uncontrolled infections

- DONOR: Malignancy within 10 years prior to donation of marrow, excluding adequately
treated squamous cell skin cancer and basal cell carcinoma; treatment must have been
completed (with the exception of hormonal therapy for breast cancer) with
cure/remission status verified for at least 10 years at time of marrow harvest

- DONOR: History of or symptoms consistent with inflammatory bowel disease or a serious
autoimmune disorder

- DONOR: History of a serious disease or disorder that could be adoptively transferred
by infusion of donor hematopoietic cells

- DONOR: Failure to meet institutional criteria for donation as described in the
Standard Practice Guidelines

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival (EFS)

Outcome Description:

Defined as alive and free of active Crohn's Disease (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.

Outcome Time Frame:

At 1 year post-transplant

Safety Issue:


Principal Investigator

George McDonald

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

July 2012

Completion Date:

Related Keywords:

  • Crohn Disease
  • Crohn's Disease Allogeneic bone marrow transplantation Hematopoietic cell transplantation
  • Crohn Disease



Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109