Crohn's Allogeneic Transplant Study

NCT01570348 | Terminated Phase 2 Results DMC

• 4 other identifiers: 2551.00NCI-2011-032862551P30CA015704
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Crohn Disease

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Event-free Survival (EFS)

  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.

  At 1 year post-transplant

Secondary Outcomes (10)

• Development of Infectious Complications

  Up to 5 years

• Disease Activity

  Up to 5 years

• EFS

  Up to 5 years post-transplant

• Incidence and Severity of GVHD

  Up to 5 years

• Incidence of Disease-modifying Drugs for CD Initiated Post-transplant

  Up to 5 years

Study Arms (1)

Treatment (allogeneic BMT)

EXPERIMENTAL

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.

Procedure: Allogeneic Bone Marrow Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Drug: Mycophenolic Acid; Other: Quality-of-Life Assessment; Drug: Tacrolimus; Radiation: Total-Body Irradiation

Interventions

Allogeneic Bone Marrow Transplantation PROCEDURE

Undergo allogeneic BMT

Also known as: Allo BMT, Allogeneic BMT

Treatment (allogeneic BMT)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (allogeneic BMT)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

Treatment (allogeneic BMT)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (allogeneic BMT)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Treatment (allogeneic BMT)

Mycophenolic Acid DRUG

Given PO

Also known as: Acide mycophenolique, Acido micofenolico, Acidum mycophenolicum, Lilly-68618, Ly 68618, MPA, Myfortic

Treatment (allogeneic BMT)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (allogeneic BMT)

Tacrolimus DRUG

Given IV or PO

Also known as: FK 506, Fujimycin, Prograf, Protopic

Treatment (allogeneic BMT)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Treatment (allogeneic BMT)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)
• 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
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• McDonald GB, Landsverk OJB, McGovern DPB, Aasebo A, Paulsen V, Haritunians T, Reims HM, McLaughlin BM, Zisman T, Li D, Elholm ETMM, Jahnsen FL, Georges GE, Gedde-Dahl T. Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease. Heliyon. 2024 Jan 3;10(1):e24026. doi: 10.1016/j.heliyon.2024.e24026. eCollection 2024 Jan 15.

  PMID: 38283244 DERIVED

MeSH Terms

Conditions

Crohn Disease

Interventions

Cyclophosphamide; fludarabine phosphate; Mycophenolic Acid; Tacrolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques

Results Point of Contact

• Title: Dr. George Georges
• Organization: FHCRC

ggeorges@fredhutch.org

(206) 667-6886

Study Officials

• George Georges

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 2, 2012
• First Posted: April 4, 2012
• Study Start: July 17, 2012
• Primary Completion: February 3, 2019
• Study Completion: October 30, 2019
• Last Updated: February 17, 2020
• Results First Posted: February 17, 2020

Record last verified: 2020-02

Locations

US (1)