Allogeneic Hematopoietic Cell Transplantation for Severe Systemic Sclerosis

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT00622895
• Date of registration: 22/02/2008
• Prospective Registration: No
• Primary sponsor: Fred Hutchinson Cancer Research Center
• Public title: Allogeneic Hematopoietic Cell Transplantation for Severe Systemic Sclerosis
• Scientific title: Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Patients With Severe Systemic Sclerosis
• Date of first enrolment: September 1, 2006
• Target sample size: 3
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT00622895
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United States

Contacts

• Name: George Georges
• Affiliation: Fred Hutch/University of Washington Cancer Consortium

Key inclusion & exclusion 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 4: Patients who meet group 1 inclusion criteria but may have FVC or
DLCO-adjusted less than 70% plus have had an adverse event on cyclophosphamide
preventing its further use (specifically hemorrhagic cystitis, leukopenia with white
blood cell [WBC]< 2000 or absolute neutrophil count [ANC] < 1000 or platelet count <
100,000).

- 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 w


Age minimum: N/A
Age maximum: 70 Years
Gender: All

Health Condition(s) or Problem(s) studied

Severe Systemic Sclerosis

Systemic Scleroderma

Intervention(s)

Drug: fludarabine phosphate

Procedure: quality-of-life assessment

Drug: tacrolimus

Other: laboratory biomarker analysis

Drug: Mycophenolic Acid

Other: flow cytometry

Procedure: biopsy

Procedure: bone marrow transplantation

Radiation: total-body irradiation

Procedure: reduced intensity allogeneic hematopoietic stem cell transplantation

Primary Outcome(s)

Event-free Survival (EFS) [Time Frame: 2 years]

Secondary Outcome(s)

Quality of Life as Assessed by the Medical Outcome Short Form (36) Health Survey Instrument (SF-36) [Time Frame: Up 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 [Time Frame: Up to 5 years]

Incidence of Graft Rejection [Time Frame: Up to day +56]

Overall Survival [Time Frame: Up to 5 years]

The Percent of Participants With Definite and Probable Viral, Fungal, and Bacterial Infections [Time Frame: Up to 5 years]

EFS [Time Frame: 5 years]

Incidence and Severity of Graft-versus-host Disease (GVHD) [Time Frame: Up to 5 years post-transplant]

Quality of Life as Assessed by the Modified Scleroderma Health Assessment Questionnaire (SHAQ) [Time Frame: Up to 5 years]

Treatment-related Mortality [Time Frame: From time of transplant to 5 years]

Skin Score [Time Frame: Up to 5 years post-transplant]

Incidence of Disease-modifying Antirheumatic Drugs (DMARDs) Initiated Post Transplant to Modify Disease [Time Frame: Up to 5 years post-transplant]

Secondary ID(s)

2067.00

NCI-2011-01352

R01AI041721

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

National Institute of Allergy and Infectious Diseases (NIAID)

Results

• Results available: Yes
• Date Posted: 04/06/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT00622895