Scleroderma Treatment With Autologous Transplant (STAT) Study

This study has suspended participant recruitment.
(Temporary suspension of enrollment for administrative reasons)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01413100
First received: August 8, 2011
Last updated: February 4, 2014
Last verified: February 2014
  Purpose

This phase II trial studies how well giving cyclophosphamide and anti-thymocyte globulin together followed by peripheral blood stem cell transplant (PBSCT) and mycophenolate mofetil works in treating patients with systemic scleroderma (SSc). Stem cells are collected from the patient's blood and stored prior to treatment. To store the stem cells patients are given colony-stimulating factors, such as filgrastim (G-CSF) or chemotherapy (cyclophosphamide) to help stem cells move from the bone marrow to the blood so they can be collected and stored. After storage, patients are then given high-dose chemotherapy, cyclophosphamide, and immunosuppression with anti-thymocyte globulin to suppress the immune system to prepare for the transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and immunosuppression. After the stem cells have "engrafted" and have matured enough to support the immune system at approximately 2-3 months, patients are given a medication called mycophenolate mofetil (MMF) or Myfortic. This medication is given to prevent worsening or reactivation of SSc and is referred to as maintenance therapy.


Condition Intervention Phase
Systemic Scleroderma
Procedure: peripheral blood stem cell transplantation
Drug: cyclophosphamide
Biological: anti-thymocyte globulin
Other: questionnaire administration
Other: laboratory biomarker analysis
Procedure: quality-of-life assessment
Biological: filgrastim
Procedure: autologous hematopoietic stem cell transplantation
Drug: mycophenolate mofetil
Drug: plerixafor
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Multi-Center Study of High-Dose Cyclophosphamide and Antithymocyte Globulin Followed by Autologous Hematopoietic Cell Transplantation With Post Transplant Maintenance for the Treatment of Systemic Sclerosis

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • EFS of patients undergoing chemotherapy and transplant [ Time Frame: At 5 years ] [ Designated as safety issue: No ]
    An event is defined as death, respiratory failure, renal failure, or the occurrence of cardiomyopathy sustained for at least 3 months despite therapy. Treated as a binary outcome.


Secondary Outcome Measures:
  • Overall survival [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
  • Non-progression mortality [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
  • Disease progression [ Time Frame: 6 months and then annually for 5 years ] [ Designated as safety issue: No ]
  • Time to treatment failure [ Time Frame: The time interval between transplant (day 0) and the initial visit at which death or the qualifying event first occurs, assessed up to 5 years ] [ Designated as safety issue: No ]
  • Improvement in pulmonary function [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Evaluated by using DLCO and FVC. Improvement is indicated by an increase of > 15% in DLCO, or FVC (actual change in % predicted units) sustained for >= 3 months. Analyzed as an ordinal outcome.

  • Improvement in pulmonary function [ Time Frame: 1 month ] [ Designated as safety issue: No ]
    Evaluated by using DLCO and FVC. Improvement is indicated by an increase of > 15% in DLCO, or FVC (actual change in % predicted units) sustained for >= 3 months. Analyzed as an ordinal outcome.

  • Improvement in pulmonary function [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Evaluated by using DLCO and FVC. Improvement is indicated by an increase of > 15% in DLCO, or FVC (actual change in % predicted units) sustained for >= 3 months. Analyzed as an ordinal outcome.

  • Improvement in pulmonary function [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
    Evaluated by using DLCO and FVC. Improvement is indicated by an increase of > 15% in DLCO, or FVC (actual change in % predicted units) sustained for >= 3 months. Analyzed as an ordinal outcome.

  • Improvement in pulmonary function [ Time Frame: Annually for 5 years ] [ Designated as safety issue: No ]
    Evaluated by using DLCO and FVC. Improvement is indicated by an increase of > 15% in DLCO, or FVC (actual change in % predicted units) sustained for >= 3 months. Analyzed as an ordinal outcome.

  • HRQOL [ Time Frame: Annually for 5 years ] [ Designated as safety issue: No ]
    Measured by the SF-36, the PROMIS-29 version 1.0, the SHAQ, and the SGRQ.

  • Change in renal function over time [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Measured by serum creatinine.

  • Change in renal function over time [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Measured by serum creatinine.

  • Change in renal function over time [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
    Measured by serum creatinine.

  • Change in renal function over time [ Time Frame: Annually for 5 years ] [ Designated as safety issue: No ]
    Measured by serum creatinine.

  • Change in cardiac function [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    Measured by ejection fraction on echocardiogram (percentage).

  • Change in cardiac function [ Time Frame: Year 2 ] [ Designated as safety issue: No ]
    Measured by ejection fraction on echocardiogram (percentage).

  • Change in cardiac function [ Time Frame: Year 3 ] [ Designated as safety issue: No ]
    Measured by ejection fraction on echocardiogram (percentage).

  • Change in cardiac function [ Time Frame: Year 4 ] [ Designated as safety issue: No ]
    Measured by ejection fraction on echocardiogram (percentage).

  • Change in cardiac function [ Time Frame: Year 5 ] [ Designated as safety issue: No ]
    Measured by ejection fraction on echocardiogram (percentage).

  • Treatment-related mortality [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
    Defined by death occurring at any time after start of mobilization procedure to day +90 after autologous HCT and definitely or probably resulting from treatment given in the study.

  • All-cause mortality [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
    Defined as any death.

  • Regimen-related toxicities [ Time Frame: Up to 1 year post-transplant ] [ Designated as safety issue: No ]
    Defined as adverse events (AEs) >= Grade 3 and assessed by the investigator as 1 of the following: unrelated, unlikely, or possibly related to treatment; probably related to treatment; definitely related to treatment.

  • Infectious complications [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
  • Initiation of putative disease-modifying antirheumatic drugs (DMARDS) to modify disease [ Time Frame: After randomization ] [ Designated as safety issue: No ]
  • Health care utilization as assessed by UCSD Healthcare Utilization surveys [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
    UCSD healthcare utilization is a self-report instrument that asks the patient about outpatient and inpatient visits, prescription and non-prescription medications, any surgeries, and major medical expenses during the last 3 months.

  • Work productivity Survey (WPS) [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
    The first question assesses employment status, type of job for the employed (non-manual, manual or mixed manual/non-manual) and the status of those unemployed (homemaker, retired, student, unable to work due to SSc, unable to work due to non-SSc health problems, or other, i.e. volunteer). The next 3 questions apply only to employed patients and assess absenteeism (full days of work missed due to SSc), presenteeism (days with work productivity reduced by greater than or equal to 50%), and how much SSc interfered with work productivity on a scale of 0-10.


Estimated Enrollment: 30
Study Start Date: September 2011
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (HDIT autologous PBSCT)

STEM CELL MOBILIZATION AND PREPARATION: Patients receive filgrastim SC on mobilization days 1-4 followed by apheresis until a target dose of CD34+ cells >= 2.5 x 10^6/kg are collected. Patients difficult to mobilize with filgrastim alone receive cyclophosphamide IV or *plerixafor SC on mobilization days 1-2 and filgrastim SC on mobilization days 5-7.

HDIT CONDITIONING: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days -5 to -2 and anti-thymocyte globulin IV on days -5, -3, -1, 1, 3, and 5.

TRANSPLANTATION: Patients undergo autologous PBSCT on day 0.

MAINTENANCE THERAPY: Beginning 2-3 months after transplant, patients receive mycophenolate mofetil PO BID for 2 years.

Procedure: peripheral blood stem cell transplantation
Undergo autologous PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin
Other: questionnaire administration
Ancillary studies
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous PBSCT
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: plerixafor
Given SC
Other Names:
  • AMD 3100
  • Mozobil

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and potential efficacy of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (HCT) (without cluster of differentiation [CD]34-selection) and maintenance therapy with mycophenolate mofetil (MMF) in systemic scleroderma (SSc) patients by evaluating the effects on event-free survival (EFS) at 5 years posttransplant.

SECONDARY OBJECTIVES:

I. To evaluate safety of HDIT followed by autologous HCT as determined by regimen-related toxicities, infectious complications, treatment-related mortality, overall total mortality, and time to engraftment.

II. To evaluate treatment effect on disease activation/progression.

III. To evaluate health-related quality of life (HRQOL) using Short Form 36 (SF-36), the St. George's Respiratory Questionnaire (SGRQ), the modified scleroderma health assessment questionnaire (SHAQ), and PROMIS version (v) 1.0 measures.

IV. To assess work productivity (Work Productivity Survey) and health care utilization (using University of California San-Diego [UCSD] healthcare utilization).

OUTLINE:

STEM CELL MOBILIZATION AND PREPARATION: Patients receive filgrastim subcutaneously (SC) on mobilization days 1-4 followed by apheresis until a target dose of CD34+ cells >= 2.5 x 10^6/kg are collected. Patients difficult to mobilize with filgrastim alone receive cyclophosphamide intravenously (IV) or *plerixafor subcutaneously (SC) on mobilization days 1-2 and filgrastim SC on mobilization days 5-7.

HDIT CONDITIONING: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days -5 to -2 and anti-thymocyte globulin IV on days -5, -3, -1, 1, 3, and 5.

TRANSPLANTATION: Patients undergo autologous PBSCT on day 0.

MAINTENANCE THERAPY: Beginning 2-3 months after transplant, patients receive mycophenolate mofetil orally (PO) twice daily (BID) for 2 years.

NOTE: * Plerixafor is an alternative to the cyclophosphamide-based mobilization.

After completion of study treatment, patients are followed at 1 month, weeks 12 and 26, and then annually for 5 years.

  Eligibility

Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • GROUP 1:

    • Patients must have 1) both a and b below; and 2) either c, or d

      • a) Diffuse cutaneous scleroderma as defined by skin thickening proximal to the elbows and knees and/or involving the torso in addition to distal extremity involvement; a skin score will be obtained but not used to determine eligibility
      • b) Duration of systemic sclerosis =< 7 years from the onset of first non-Raynaud's symptom; for those patients with disease activity between 5-7 years from the onset of first non-Raynaud's symptom, recent progression or activity of disease must be documented
      • c) Presence of SSc-related pulmonary disease with forced vital capacity (FVC) < 80% or hemoglobin-adjusted diffusing capacity for carbon monoxide (DLCO) < 70% of predicted AND evidence of alveolitis by high-resolution chest computed tomography (CT) scan and/or by bronchoalveolar lavage (BAL) (if high resolution computed tomography [HRCT] fails to show ground glass, then BAL for diagnosis of alveolitis must be confirmed); alveolitis by BAL cell count will be defined based on a BAL cell differential count (> 3% neutrophils and/or > 2% eosinophils) from any lavaged lobe
      • d) History of SSc-related renal disease that may not be active at the time of screening; stable serum creatinine must be documented for a minimum of 3 months post-renal crisis at the time of the baseline visit; history of scleroderma hypertensive renal crisis is included in this criterion and is defined as follows:

        • History of new-onset hypertension based on any of the following (measurements must be repeated and confirmed at least 2 hours apart within 3 days of first event-associated observation, with a change from baseline):

          • Systolic blood pressure (SBP) >= 140 mmHg
          • Diastolic blood pressure (DBP) >= 90 mmHg
          • Rise in SBP >= 30 mmHg compared to baseline
          • Rise in DBP >= 20 mmHg compared to baseline
        • AND one of the following 5 laboratory criteria:

          • Increase of >= 50 % above baseline in serum creatinine

            • Proteinuria: >= 2+ by dipstick confirmed by protein:creatinine ratio > 2.5
            • Hematuria: >= 2+ by dipstick or > 10 red blood cell (RBC)s/hematopoietic-promoting factor (HPF) (without menstruation)
            • Thrombocytopenia: < 100,000 platelets/mm^3
            • Hemolysis: by blood smear or increased reticulocyte count
        • The above definition of SSc hypertensive renal crisis is independent of whether concomitant anti-hypertensive medications are used
        • Subjects who present with solely skin and renal disease in the absence of other organ involvement, except classic SSc renal crisis as described above and including non-hypertensive renal crisis, must see a nephrologist to confirm that their renal disease is secondary to only SSc
        • Note: Subjects may be re-screened if they fail to meet inclusion criteria on initial evaluation
  • GROUP 2:

    • Progressive pulmonary disease as defined by a decrease in the FVC or DLCO-adjusted by 10 or 15 percent or greater, respectively, from a prior FVC or DLCO-adjusted in the previous 18-month period
    • Patients will have diffuse cutaneous disease and may have both FVC and DLCOcorr >= 70% at screening for the study
    • Patients must also have evidence of alveolitis as defined by abnormal chest computed tomography (CT) or bronchoalveolar lavage (BAL)
  • GROUP 3: Diffuse scleroderma with disease duration =< 2 years since development of first sign of skin thickening plus modified Rodnan skin score >= 25 plus either

    • Erythrocyte sedimentation rate (ESR) > 25 mm/1st hour and/or hemoglobin (Hb) < 11 g/dL, not explained by causes other than active scleroderma
    • Lung involvement (either FVC or DLCO < 80% and evidence of interstitial lung disease by CT scan or alveolitis by BAL)
  • GROUP 4: Diffuse scleroderma with disease duration =< 2 years and skin score >= 30
  • GROUP 5:

    • Limited cutaneous scleroderma and SSc-related pulmonary disease with FVC < 80% or hemoglobin-adjusted DLCO < 70% of predicted
    • AND evidence of alveolitis by high-resolution chest CT scan and/or by BAL (if HRCT fails to show ground glass, then BAL for diagnosis of alveolitis must be confirmed)
    • Alveolitis by BAL cell count will be defined based on a BAL cell differential count (> 3% neutrophils and/or > 2% eosinophils) from any lavaged lobe
  • GROUP 6: Progressive gastrointestinal disease as defined by all of the following items:

    • Disease duration of scleroderma =< 2 years.
    • Documented severe malabsorption syndrome requiring nutritional support; severe malabsorption syndrome is > 10% weight loss and on total parenteral nutrition (TPN) or enteral feedings
    • High score on distention/ bloating scale (>= 1.60 out of 3.00) on gastrointestinal (GI) questionnaire

Exclusion Criteria:

  • Subjects with pulmonary, cardiac, hepatic, or renal impairment that would limit their ability to receive cytoreductive therapy and compromise their survival; this includes, but is not restricted to, subjects with any of the following:
  • Pulmonary dysfunction defined as:

    • Severe pulmonary dysfunction with (1) a hemoglobin corrected DLCO < 40% of predicted at the Baseline Screening visit, or (3) FVC < 45% of predicted Baseline Screening visit, or
    • Partial pressure (pO2) < 70 mmHg or pCO2 >= 45 mmHg without supplemental oxygen, or
    • O2 saturation < 92% at rest without supplemental oxygen as measured by forehead pulse oximeter
  • Significant pulmonary artery hypertension (PAH) defined as:

    • Peak systolic pulmonary artery pressure > 50 mmHg by resting echocardiogram will require right heart catheterization; if pulmonary artery pressure (PAP) is not evaluable on echocardiogram due to lack of a Tricuspid regurgitant jet, then normal anatomy and function as evidenced by normal right atrium and ventricle size, shape and wall thickness and septum shape must be documented to rule-out PAH; otherwise, right heart catheterization is indicated; prior history of PAH but controlled with medications will not exclude patients from the protocol; PAH is considered controlled with medications if peak systolic pulmonary artery pressure is < 45 mmHg or mean pulmonary artery pressure by right heart catheterization is < 30 mmHg at rest
    • Mean pulmonary artery pressure by right heart catheterization exceeding 30 mmHg at rest; if mean PAP is elevated and pulmonary vascular resistance and transpulmonary gradient are normal then the patient is eligible for the protocol
    • New York Heart Association (NYHA)/World Health Organization Class III or IV
  • Cardiac: Uncontrolled clinically significant arrhythmias; clinical evidence of significant congestive heart failure (CHF) (NYHA Class III or IV); left ventricular ejection fraction (LVEF) < 50% by echocardiogram or prior insertion of a pacemaker or cardioverter-defibrillator
  • History/presence of arrhythmia (even controlled) on chemical anti-arrhythmic(s) must have cardiac consult to ensure the subject could safely proceed with protocol requirements
  • Significant renal pathology defined as:

    • Estimated creatinine clearance (CrCl) < 40 mL/min (using Cockcroft-Gault formula based on actual body weight) and serum creatinine > 2.0 mg/dL; OR
    • Active, untreated SSc renal crisis at the time of enrollment; presence of nephrotic range proteinuria (defined as >= 3.5 gms/24 hours, or protein:creatinine ratio >= 3.5), active urinary sediment, urinary RBCs > 25 per HPF, or red cell casts require further investigation by a nephrologist to rule out glomerulonephritis, overlap syndromes, or other causes of renal disease in all subjects; subjects with glomerulonephritis or overlap syndromes will be excluded
  • Hepatic: Active hepatitis (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or bilirubin > 2 times the upper limit of normal [ULN]) or evidence of moderate to severe periportal fibrosis by liver biopsy
  • Active or clinically significant Gastric Antral Vascular Ectasia (GAVE, "watermelon stomach")
  • Unwilling or unable to discontinue disallowed disease-modifying antirheumatic drugs (DMARDs) for treatment of SSc prior to mobilization
  • History or presence of a 2nd autoimmune disease requiring immunosuppressive therapy that has substantial risk of immunosuppressive treatment beyond transplant with the following exceptions:

    • History and/or presence of Sjogren's Syndrome is allowed
    • Stable myositis (A history of myositis that is clinically stable as defined by lack of progressive proximal muscle weakness and a stable or decreasing creatine phosphokinase [CPK] < 3 x ULN) is allowed
    • The presence of anti-double stranded (ds)-deoxyribonucleic acid (DNA) without clinical systemic lupus erythematosus in a patient with a diagnosis of otherwise "pure" SSc is allowed
    • Concomitant rheumatoid arthritis without extra-articular disease characteristic of rheumatoid arthritis is allowed
  • Active uncontrolled infection that would be a contraindication to safe use of high-dose therapy
  • Positive study for Hepatitis B surface antigen or Hepatitis B or C confirmed by polymerase chain reaction (PCR)
  • Positive serology for human immunodeficiency virus (HIV)
  • Absolute neutrophil count (ANC) < 1500 cells/uL
  • Platelets < 100,000 cells/uL
  • Hematocrit < 27%
  • Hemoglobin < 9.0 g/dL
  • Malignancy within the 2 years prior to entry in study, 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 prior to entry in this study
  • Presence of other comorbid illnesses with an estimated median life expectancy < 5 years
  • Evidence of myelodysplasia (MDS); subjects with history of receiving any prior chemotherapy and/or radiotherapy for the treatment of malignant disease, history of greater than 2 months total prior cyclophosphamide for any condition (regardless of dose and route) and/or subjects presenting with abnormal peripheral blood counts require unilateral bone marrow aspiration for pathology, flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH) MDS panel (per institutional profile) to rule out MDS
  • Pregnancy
  • Inability to give voluntary informed consent
  • Unwilling to use contraceptive methods for at least 15 months after starting treatment
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01413100

Locations
United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States, 80218
United States, Massachusetts
Boston University School of Medicine
Boston, Massachusetts, United States, 02118-2393
United States, Michigan
University of Michigan University Hospital
Ann Arbor, Michigan, United States, 48109
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: George Georges Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01413100     History of Changes
Other Study ID Numbers: 2533.00, NCI-2011-01190, P30CA015704
Study First Received: August 8, 2011
Last Updated: February 4, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Scleroderma, Localized
Connective Tissue Diseases
Skin Diseases
Antilymphocyte Serum
Cyclophosphamide
Mycophenolate mofetil
Immunoglobulins
Lenograstim
Mycophenolic Acid
JM 3100
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Enzyme Inhibitors
Adjuvants, Immunologic
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 15, 2014