Allogeneic Hematopoietic Cell Transplantation for Severe Systemic Sclerosis

NCT ID: NCT00622895

Last Updated: 2018-06-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-09-01
• Study Completion Date: 2017-08-01

Brief Summary

The purpose of the study is to examine the safety and effectiveness of a reduced intensity conditioning regimen and allogeneic bone marrow transplant for people with systemic sclerosis. In an allogeneic bone marrow transplant procedure, bone marrow is taken from a healthy donor and transplanted into the patient. Bone marrow can be donated by a family member or an unrelated donor who is a complete tissue type match.

Participants will receive the chemotherapy and low dose radiation conditioning regimen consisting of the following: Fludarabine will be given intravenously for 5 days. Cyclophosphamide will be given intravenously on the first and second day. After completing the fludarabine and cyclophosphamide, patients will receive a single low dose of total body irradiation. The next day, patients will receive the allogeneic bone marrow transplant. On the third and fourth day after the transplant, patients will receive high dose intravenous cyclophosphamide. This is given to help prevent two complications: (1) graft rejection, which occurs when the body's immune system rejects the donor bone marrow, and (2) graft-versus-host disease (GVHD), which is when the donor immune cells attack the patient's normal tissues. On the fifth day after the transplant, patients will start receiving two additional medications: tacrolimus and mycophenolic acid (MPA, Myfortic), to help prevent GVHD. Patients will receive mycophenolic acid for about 5 weeks and tacrolimus for about 6 months. Also beginning on the fifth day after the transplant, patients will receive daily injections of a growth factor called granulocyte-colony stimulating factor (G-CSF), which is a protein that increases the white blood cell count; G-CSF will be continued until the patient's white blood cell count has returned to normal levels.

Patients will remain closely monitored either in the outpatient clinic setting or in the hospital for approximately 2-3 months after the transplant, but possibly longer if there are complications. Follow-up study visits will occur at 6 months and then at 1, 2, 3, 4, and 5 years after the transplant. Study researchers will keep track of the patient's medical condition after leaving the transplant center by phone calls or mailings to patients and their doctors once a year for the rest of the study participants' lives.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety and potential efficacy of reduced intensity conditioning with fludarabine/cyclophosphamide/low-dose total body irradiation (TBI) and allogeneic hematopoietic cell transplantation (HCT) for the stabilization or regression of disease manifestations of severe systemic sclerosis (SSc).

SECONDARY OBJECTIVES:

I. To determine whether stable allogeneic donor engraftment can be safely established with reduced intensity conditioning followed by matched sibling or unrelated donor bone marrow transplantation in patients with severe SSc.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) on days -6, -5, -4, -3 and -2 and Cyclophosphamide IV on days -6, -5, and undergo 2 Gray TBI on day -1. Patients receive human leukocyte antigen (HLA)-matched donor bone marrow transplantation on day 0. Patients then receive cyclophosphamide IV on days +3 and +4, and beginning day +5 they start tacrolimus orally (PO) and enteric coated mycophenolic acid.

After completion of initial study treatment, patients are followed up at 6 months and then annually for 5 years.

Conditions

Systemic Scleroderma; Severe Systemic Sclerosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment: allogeneic UCB after reduced intensity conditioning

Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.

Group Type: EXPERIMENTAL

fludarabine phosphate

Intervention Type: DRUG

Given IV

Mycophenolic Acid

Intervention Type: DRUG

Given PO

tacrolimus

Intervention Type: DRUG

Given PO

total-body irradiation

Intervention Type: RADIATION

Undergo TBI

bone marrow transplantation

Intervention Type: PROCEDURE

Undergo transplantation

reduced intensity allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

Undergo transplantation

quality-of-life assessment

Intervention Type: PROCEDURE

Ancillary studies

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

flow cytometry

Intervention Type: OTHER

Correlative studies

biopsy

Intervention Type: PROCEDURE

Punch biopsy of skin involved with scleroderma

Interventions

fludarabine phosphate

Given IV

Intervention Type: DRUG

Mycophenolic Acid

Given PO

Intervention Type: DRUG

tacrolimus

Given PO

Intervention Type: DRUG

total-body irradiation

Undergo TBI

Intervention Type: RADIATION

bone marrow transplantation

Undergo transplantation

Intervention Type: PROCEDURE

reduced intensity allogeneic hematopoietic stem cell transplantation

Undergo transplantation

Intervention Type: PROCEDURE

quality-of-life assessment

Ancillary studies

Intervention Type: PROCEDURE

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

flow cytometry

Correlative studies

Intervention Type: OTHER

biopsy

Punch biopsy of skin involved with scleroderma

Intervention Type: PROCEDURE

Other Intervention Names

2-F-ara-AMP; Beneflur; Fludara; Myfortic; FK 506; Prograf; TBI; stem cell transplantation; progenitor cell transplantation; transplantation; quality of life assessment; biopsies

Eligibility Criteria

Inclusion Criteria

• Patients eligible for the study must have a human leukocyte antigen (HLA)-identical sibling or HLA-matched unrelated bone marrow donor available and willing to donate.
• Patients with severe SSc as defined by the American College of Rheumatology and at high-risk for a fatal outcome based on the following prognostic factors in groups 1-5:
• Group 1: Patients must have 1) both a and b below; and 2) at least one of c, d or e:

• a. diffuse cutaneous scleroderma with skin score of greater than or equal to 16 (modified Rodnan scale [mRSS]).
• b. duration of systemic sclerosis less than or equal to 7 years from the onset of first non-Raynaud's symptom.
• c. presence of interstitial lung disease (either forced vital capacity [FVC] or corrected diffusing capacity of the lung for carbon monoxide [DLCOcorr] less than 70 % of predicted) and evidence of alveolitis (abnormal bronchoalveolar lavage (BAL) or high resolution chest computed tomography [CT] scan) after treatment with intravenous cyclophosphamide greater than or equal 2 grams given over at least a 3 month period; for patients not able to adequately complete pulmonary function tests (PFT), there must be evidence of progressive disease on chest CT.
• d. left heart failure with left ventricular ejection fraction (LVEF) < 50% (that has responded to treatment targeted to scleroderma); 2nd or 3rd atrioventricular (AV) block with other evidence of cardiomyopathy related to SSc; myocardial disease not secondary to SSc must be excluded by a cardiologist.
• e. history of SSc-related renal disease that is not active at the time of screening; history of scleroderma hypertensive renal crisis is included in this criterion.
• Group 2: Progressive pulmonary disease as defined by a decrease in the FVC or DLCOcorr by 15 percent or greater compared to a prior FVC or DLCOcorr in the previous twelve month period; in addition, patients may have either less skin involvement than group 1 (mRSS less than 16) and the FVC or DLCOcorr is less than 70% or both FVC and DLCOcorr greater than or equal to 70% if they have diffuse cutaneous disease (mRSS greater than 16) at screening for the study; patients must also have evidence of alveolitis as defined by abnormal chest CT or BAL; for patients not able to adequately complete PFT, there must be evidence of progressive disease on chest CT.
• Group 3: Have progressive active SSc after prior autologous transplant based on the presence of progressive pulmonary disease; this will be defined by a decrease in the FVC or DLCO adjusted since prior autologous transplant of 15 percent or greater of the pre-transplant percent predicted value, in addition to evidence of alveolitis as defined by chest CT changes or BAL. If patients had prior autologous HCT on the "Scleroderma: Cyclophosphamide Or Transplantation" (SCOT) clinical trial, they must have failed based on the defined study endpoints and be approved by the protocol principal investigator (PI).
• Group 5: Diffuse scleroderma with disease duration less than or equal to 2 years since development of first sign of skin thickening plus modified Rodnan skin score greater than or equal to 25 plus erythrocyte sedimentation rate (ESR) > 25 mm/1st hour and/or hemoglobin (Hb) < 11 g/dL, not explained by causes other than active scleroderma.
• Unless patients have a DLCO-adjusted less than 45%, patients in all groups must have failed either oral or intravenous cyclophosphamide regimen defined as: IV cyclophosphamide administration for at least > 3 months between first and last cyclophosphamide dose at a total cumulative IV dose of at least 2 grams, oral cyclophosphamide administration for > 4 months regardless of dose, or combination of oral and IV cyclophosphamide for at least > 6 months independent of dose.
• DONOR: HLA genotypically identical sibling or unrelated donor; unrelated donors are required to be matched by standard molecular methods at the intermediate resolution level at HLA-A, B, C and DRB1 and the allele level at DQB1.
• DONOR: Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB) guidelines
• DONOR: Bone marrow is the preferred cell source

Exclusion Criteria

• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following transplant
• Evidence of ongoing active infection
• Pregnancy
• Patients with a creatinine clearance < 60 ml/min/1.73 m^2 body surface area
• Uncontrolled clinically significant arrhythmias
• Clinical evidence of significant congestive heart failure (CHF) (New York Heart Association [NYHA] Class III or IV)
• LVEF < 45% by echocardiogram
• Severe pulmonary dysfunction with a hemoglobin corrected DLCO < 30% or FVC < 40% of predicted or O2 saturation < 92% at rest without supplemental oxygen
• Significant uncontrolled pulmonary hypertension defined as: Pulmonary artery peak systolic pressure > 55 mmHg by echocardiogram, or pulmonary artery peak systolic pressure 45-55 mmHg by echocardiogram and mean pulmonary artery pressure by right heart catheterization exceeding 25 mmHg at rest (or 30 mmHg with exercise); or NYHA/World Health Organization (WHO), Class III or IV
• Active hepatitis or liver biopsy evidence of cirrhosis or periportal fibrosis; liver function tests: total bilirubin > 2 x the upper limit of normal and/or serum glutamic pyruvate transaminase (SGPT) and SGPT > 4 x the upper limit of normal
• Patients with poorly controlled hypertension
• Patients whose life expectancy is severely limited by illness other than autoimmune disease
• Patients with poorly controlled bleeding from gastric antral vascular ectasia (GAVE) or other gastrointestinal (GI) sites
• Untreated psychiatric illness, drug/alcohol abuse
• Inability to give voluntary informed consent or guardian's informed consent
• Demonstrated lack of compliance with prior medical care
• Malignancy within the 2 years prior to treatment, excluding adequately treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ; treatment must have been completed (with the exception of hormonal therapy for breast cancer) with cure/remission status verified for at least 2 years at time of treatment
• Human immunodeficiency virus (HIV) seropositivity
• DONOR: Identical twin
• DONOR: Current pregnancy
• DONOR: HIV seropositivity
• DONOR: Deemed medically unable to undergo bone marrow harvesting
• DONOR: Current serious systemic illness including uncontrolled infections
• DONOR: Failure to meet institutional criteria for donation as described in the Standard Practice Guidelines

• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

George Georges

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

George Georges

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

Colorado Blood Cancer Institute

Denver, Colorado, United States

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

Other Identifiers

NCI-2011-01352

Identifier Type: REGISTRY

Identifier Source: secondary_id

R01AI041721

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2067.00

Identifier Type: -

Identifier Source: org_study_id