Crohn's Allogeneic Transplant Study (CATS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01570348
First received: April 2, 2012
Last updated: May 2, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Crohn Disease
Drug: cyclophosphamide
Radiation: total-body irradiation
Drug: tacrolimus
Procedure: quality-of-life assessment
Other: laboratory biomarker analysis
Drug: fludarabine phosphate
Procedure: allogeneic bone marrow transplantation
Drug: mycophenolic acid
Drug: mycophenolate mofetil
Phase 2

Study Type: Interventional
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 CROHNS DISEASE: A PHASE 2 STUDY

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Event-free survival (EFS) [ Time Frame: At 1 year post-transplant ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 80 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.


Estimated Enrollment: 12
Study Start Date: July 2012
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 continuously 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: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: laboratory biomarker analysis
Correlative studies
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic BMT
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Drug: mycophenolic acid
Given PO
Other Names:
  • acide mycophenolique
  • acido micofenolico
  • acidum mycophenolicum
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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; 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 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:

    • Crohn disease activity index (CDAI) >= 250
    • Need for total parenteral nutrition to maintain weight
    • Recurrent intestinal inflammation caused by CD following surgical resection
  • Identification of an human leukocyte antigen (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 an HLA matched sibling
  • 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.

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01570348

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: George B. McDonald    206-667-2287    CATS@fhcrc.org   
Contact: Bernadette McLaughlin    206-667-2287    CATS@fhcrc.org   
Principal Investigator: George B. McDonald         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: George McDonald Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01570348     History of Changes
Other Study ID Numbers: 2551.00, NCI-2011-03286, 2551.00, P30CA015704
Study First Received: April 2, 2012
Last Updated: May 2, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Fred Hutchinson Cancer Research Center:
Crohn's Disease
Allogeneic bone marrow transplantation
Hematopoietic cell transplantation

Additional relevant MeSH terms:
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Cyclophosphamide
Tacrolimus
Fludarabine phosphate
Mycophenolate mofetil
Fludarabine
Mycophenolic Acid
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antibiotics, Antineoplastic
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on October 01, 2014