Allogeneic Hematopoietic Cell Transplantation for Severe Systemic Sclerosis

NCT00622895 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 2067.00NCI-2011-01352R01AI041721
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 2

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.

Conditions

Systemic Scleroderma; Severe Systemic Sclerosis

Keywords

scleroderma; systemic sclerosis

Outcome Measures

Primary Outcomes (1)

• Event-free Survival (EFS)

  The events will be defined as any one of the following: death; respiratory failure; renal failure, as defined by chronic dialysis \> or = 6 months or kidney transplantation; occurrence of cardiomyopathy, confirmed by clinical CHF (New York Class III or IV) or LVEF \< 30% by echocardiogram, sustained for at least 3 months despite therapy; organ dysfunction specific events must be documented on at least two occasions \> or = 3 months apart, or sustained for a 3-month period (documented from the first occurrence).

  2 years

Secondary Outcomes (11)

• EFS

  5 years

• Overall Survival

  Up to 5 years

• Treatment-related Mortality

  From time of transplant to 5 years

• Regimen-related Toxicity (Greater Than or Equal to Grade III) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0

  Up to 5 years

• The Percent of Participants With Definite and Probable Viral, Fungal, and Bacterial Infections

  Up to 5 years

Study Arms (1)

Treatment: allogeneic UCB after reduced intensity conditioning

EXPERIMENTAL

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.

Drug: fludarabine phosphate; Drug: Mycophenolic Acid; Drug: tacrolimus; Radiation: total-body irradiation; Procedure: bone marrow transplantation; Procedure: reduced intensity allogeneic hematopoietic stem cell transplantation; Procedure: quality-of-life assessment; Other: laboratory biomarker analysis; Other: flow cytometry; Procedure: biopsy

Interventions

fludarabine phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, Beneflur, Fludara

Treatment: allogeneic UCB after reduced intensity conditioning

Mycophenolic Acid DRUG

Given PO

Also known as: Myfortic

Treatment: allogeneic UCB after reduced intensity conditioning

tacrolimus DRUG

Given PO

Also known as: FK 506, Prograf

Treatment: allogeneic UCB after reduced intensity conditioning

total-body irradiation RADIATION

Undergo TBI

Also known as: TBI

Treatment: allogeneic UCB after reduced intensity conditioning

bone marrow transplantation PROCEDURE

Undergo transplantation

Also known as: stem cell transplantation, progenitor cell transplantation, transplantation

Treatment: allogeneic UCB after reduced intensity conditioning

reduced intensity allogeneic hematopoietic stem cell transplantation PROCEDURE

Undergo transplantation

Treatment: allogeneic UCB after reduced intensity conditioning

quality-of-life assessment PROCEDURE

Ancillary studies

Also known as: quality of life assessment

Treatment: allogeneic UCB after reduced intensity conditioning

laboratory biomarker analysis OTHER

Correlative studies

Treatment: allogeneic UCB after reduced intensity conditioning

flow cytometry OTHER

Correlative studies

Treatment: allogeneic UCB after reduced intensity conditioning

biopsy PROCEDURE

Punch biopsy of skin involved with scleroderma

Also known as: biopsies

Treatment: allogeneic UCB after reduced intensity conditioning

Eligibility Criteria

• Age: Up to 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Scleroderma, Systemic; Scleroderma, Diffuse

Interventions

fludarabine phosphate; Mycophenolic Acid; Tacrolimus; Whole-Body Irradiation; Bone Marrow Transplantation; Stem Cell Transplantation; Transplantation; Flow Cytometry; Biopsy

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques; Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Surgical Procedures, Operative; Cell Transplantation; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Cytophotometry; Fluorometry; Luminescent Measurements; Photometry; Chemistry Techniques, Analytical; Cytodiagnosis; Specimen Handling; Diagnostic Techniques, Surgical

Results Point of Contact

• Title: George E. Georges MD
• Organization: Fred Hutchinson Cancer Research Center

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: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 22, 2008
• First Posted: February 25, 2008
• Study Start: September 1, 2006
• Primary Completion: November 1, 2011
• Study Completion: August 1, 2017
• Last Updated: June 4, 2018
• Results First Posted: June 4, 2018

Record last verified: 2018-05

Locations

US (2)