Crohn's Allogeneic Transplant Study

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.

Inclusion Criteria:

- 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;
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 at or above a prednisone equivalent of 40 mg/day for at
least 2 weeks, or until drug toxicity or intolerance develops

- Methotrexate (25 mg per week for at least 3 months, or until drug toxicity or
intolerance develops) and/or a thiopurine antimetabolite (either 2.5 mg/kg
azathioprine or 1.5 mg/kg 6-mercaptopurine in patients homozygous wild-type for
the thiopurine-S-methyltransferase [TPMT] gene, or either 1.5 mg/kg azathioprine
or 1 mg/kg 6-mercaptopurine in patients heterozygous for TPMT, or doses of these
drugs capable of producing a 6-thioguanine nucleotide level of 230-400 without
producing a 6-methylmercaptopurine nucleotide level above 5700 for at least 3
months, or until drug allergy, intolerance or toxicity develops); 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-tumor necrosis factor (TNF)-alpha therapies, that is,
infliximab (at least 5 mg/kg every 8 weeks for at least 3 months, or until drug
allergy, toxicity or intolerance or anti-infliximab antibodies develop) and/or
adalimumab (at least 40 mg subcutaneously [SQ] every 2 weeks for at least 3
months, or until drug allergy, toxicity or intolerance develops) and/or
certolizumab pegol (at least 400 mg SQ every 4 weeks for at least 3 months, or
until drug allergy, toxicity or intolerance develops)

- Due to the serious risk of progressive multifocal leukoencephalopathy (PML) and
the reluctance of some patients to agree to therapy that carries such risk, prior
exposure to natalizumab is not required to meet the definition of exhaustive
pharmaceutical treatment; neither will use of natalizumab among patients who are
John Cunningham (JC) virus antibody seronegative be an exclusionary criterion

- Exhaustive surgical treatment will be defined as indicated operations for
complications of Crohn's Disease up to the point where the risks of surgery (for
example, mortality or post-operative morbidity such as short bowel syndrome or
extensive adhesions with high risk for inadvertent enterotomy) 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 Food and Drug Administration (FDA) approved for this
indication, will not be a criterion for either inclusion or exclusion

- Endoscopic and histologic evidence of active intestinal inflammation consistent with
CD; 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:

- CDAI >= 250

- Need for total parenteral nutrition to maintain weight

- Recurrent intestinal inflammation caused by CD following surgical resection

- Identification of a 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, and without nucleotide-binding oligomerization domain
containing 2 (NOD2) mutations in the case of a HLA matched sibling

- DONORS will be a 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 groups

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

Exclusion Criteria:

- 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, defined as
pulmonary disease-moderate, using pre-transplant pulmonary function testing per
the Fred Hutchinson Cancer Research Center (FHCRC) Standard Practice Manual

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

- Marrow dysfunction that poses a risk of peri-transplant mortality, defined as an
absolute neutrophil count or lymphocyte count below the lower limit of normal, or
a platelet count below 50,000/mm^3

- Poorly controlled hypertension despite appropriate therapy, defined as a
diastolic blood pressure greater than 90 mm Hg while on therapy

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

- Poorly controlled diabetes mellitus, defined as persistent hyperglycemia despite
therapy or recurrent hypoglycemia while on therapy

- 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 3 months

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

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

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

- 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

- DONOR: Identical twin

- DONOR: Pregnant or lactating females

- DONOR: HIV seropositivity or presence of HBV deoxyribonucleic acid (DNA) or HCV
ribonucleic acid (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: Homozygous NOD2 mutation

- 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