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Complete title: ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH TREATMENT-REFRACTORY CROHNS DISEASE: A PHASE 2 STUDY
|Research Study Number||2551.00|
|Principal Investigator||George McDonald, MD|
Research Study Description
Eligibility Criteria (must meet the following to participate in this study)
Genders Eligible for Study: Both
- 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:
-- a) Systemic glucocorticoids.
-- b) 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.
-- c) Use of at least two anti-TNF-alpha therapies (infliximab and/or adalimumab and/or certolizumab pegol).
-- d) 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.
-- e) 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 groups.
- DONORS will have the ability to understand and the willingness to sign a written informed consent document for bone marrow harvest.
Other eligibility criteria may apply.
Exclusions (conditions that would prevent participation in this study)
- A current complication of CD that would jeopardize survival after hematopoietic cell transplantation, including but not limited to the following:
- a) Abscess, phlegmon, necrotizing skin lesion, or inflammatory fistula
- b) Intestinal fibrotic stricture and intestinal obstruction
- c) Uncontrolled mucosal, organ, or systemic infection with a bacterial, viral, fungal, or parasitic organism
- d) 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:
- a) Renal insufficiency as defined by an estimated Glomerular Filtration Rate (GFR) < 60 mL/minute
- b) 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%
- c) Pulmonary dysfunction that poses a risk of mortality after transplant
- d) Necroinflammatory or fibrotic liver disease with evidence of liver dysfunction, including but not limited to jaundice, hepatic encephalopathy, or portal hypertension
- e) Marrow dysfunction that poses a risk of peri-transplant mortality
- f) Poorly controlled hypertension despite appropriate therapy
- g) Neurologic dysfunction that affects activities of daily living and medical care
- h) Poorly controlled diabetes mellitus
- I) 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
- 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 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 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
Other exclusion criteria may apply.
Bone Marrow and Hematopoietic Stem Cell Transplant (BMT and HSCT)
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