Phase 2 N=3 Treatment

Allogeneic Hematopoietic Cell Transplantation for Severe Systemic Sclerosis

Systemic Scleroderma · Severe Systemic Sclerosis

Bottom Line

View on ClinicalTrials.gov: NCT00622895 ↗

Enrolled (actual)

Serious AEs

66.7%

Results posted

Jun 2018

Primary outcome: Primary: Event-free Survival (EFS) — 1 Participants

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: fludarabine phosphate (Drug); Mycophenolic Acid (Drug); tacrolimus (Drug); total-body irradiation (Radiation); bone marrow transplantation (Procedure); reduced intensity allogeneic hematopoietic stem cell transplantation (Procedure); quality-of-life assessment (Procedure); laboratory biomarker analysis (Other); flow cytometry (Other); biopsy (Procedure)
Age: Pediatric, Adult, Older Adult
Sex: All
Sponsor: Fred Hutchinson Cancer Center
Primary completion: Nov 2011

Outcome Measures

Outcome	Result	p-value
PRIMARY Event-free Survival (EFS)	1	—
SECONDARY EFS	1	—
SECONDARY Overall Survival	1	—
SECONDARY Treatment-related Mortality	2	—
SECONDARY Regimen-related Toxicity (Greater Than or Equal to Grade III) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0	1; 1; 1	—
SECONDARY The Percent of Participants With Definite and Probable Viral, Fungal, and Bacterial Infections	2	—
SECONDARY Quality of Life as Assessed by the Modified Scleroderma Health Assessment Questionnaire (SHAQ)	1.125; 0.125; 3; 0.5; 3; 0	—
SECONDARY Quality of Life as Assessed by the Medical Outcome Short Form (36) Health Survey Instrument (SF-36)	49.3; 50; 50	—
SECONDARY Skin Score	17; 4	—
SECONDARY Incidence of Graft Rejection	—	—
SECONDARY Incidence and Severity of Graft-versus-host Disease (GVHD)	2; 2	—
SECONDARY Incidence of Disease-modifying Antirheumatic Drugs (DMARDs) Initiated Post Transplant to Modify Disease	0; 3	—

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.

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) 25 mm/1st hour and/or hemoglobin (Hb) 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 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 Guidel

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Data sourced from ClinicalTrials.gov (NCT00622895). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.