Scleroderma Treatment With Autologous Transplant (STAT) Study (STAT)

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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Scleroderma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Cyclophosphamide; Biological: Filgrastim; Drug: Mycophenolate Mofetil; Biological: Anti-Thymocyte Globulin; Drug: Plerixafor; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA / Jonsson Comprehensive Cancer Center
  • Colorado
    • Denver, Colorado, United States, 80217-3364
      • University of Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center, Houston
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with SSc as defined by the American College of Rheumatology with diffuse cutaneous disease (except Group 5) at risk of disease progression
• Patients must have failed a prior >= 4-mponth course of either MMF/Myfortic or cyclophosphamide before being eligible for the study (determined at >= 1 week before start of mobilization); "failure" is defined as evidence of disease progression or absence of improvement; the response prior to MMF of cyclophosphamide will be assessed by the participating site study rheumatologist
• Patients must meet eligibility in at least 1 of the following 6 groups:

• 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 or SSc-related interstitial lung disease by high-resolution chest computed tomography (CT) scan and/or by bronchoalveolar lavage (BAL) (interstitial lung disease may be nonspecific interstitial pneumonia [NSIP] or usual interstitial pneumonia [UIP]; a bronchoalveolar lavage [BAL] should be done to confirm the findings of alveolitis only if the high resolution CT scan [HRCT] fails to show findings typically associated with systemic sclerosis changes [ground glass NSIP, UIP, SSc related interstitial lung disease]); 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/interstitial lung disease by high-resolution chest CT scan and/or by BAL (interstitial lung disease may be nonspecific interstitial pneumonia [NSIP] or usual interstitial pneumonia [UIP]; A bronchoalveolar lavage [BAL] should be done to confirm the findings of alveolitis only if the high resolution CT scan [HRCT] fails to show findings typically associated with systemic sclerosis changes [ground glass, NSIP, UIP, SSc related interstitial lung disease])
  • 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
• 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
• History of smoking tobacco (or other related/herbal products) in the prior 3 months
• History of prior autologous hematopoietic cell transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Filgrastim XM02; Tbo-filgrastim; Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Biological: Anti-Thymocyte Globulin; Given IV; Other Names: ATGAM; ATG; Antithymocyte Globulin; Antithymocyte Serum; ATS; Thymoglobulin; Drug: Plerixafor; Given SC; Other Names: Mozobil; AMD 3100; JM-3100; SDZ SID 791; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous PBSCT; Other Names: Autologous Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EFS of Patients Undergoing Transplant	Event Free Survival (EFS) was defined as survival without meeting the protocol defined endpoint of organ injury (kidney injury requiring renal replacement dialysis for >6 months, sustained LVEF <30%, or sustained decline of FVC >20%).	At 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality	Defined as any death.	At 5 years
The Number of Participants With Stable or Improved LVEF	By echocardiogram, left ventricle ejection fraction (LVEF) greater than or equal to 30% for greater than or equal to 3 months	From baseline to year 5
Number of Participants Requiring Dialysis	Measured by requiring chronic dialysis greater than or equal to 6 months after transplant or required kidney transplant.	From baseline to year 5
The Number of Participants With Disease Progression	Chronic renal dysfunction requiring dialysis greater than or equal to 6 months post transplant or requiring kidney transplant, sustained by echo LVEJF <30% for at least 3 months post transplant, or sustained greater than or equal to 3 months decrease of FVC on pulmonary function test (PFT) > 20% post transplant.	baseline to year 5
The Number of Participants Who Completed ALL Health Care Utilization as Assessed by UCSD Healthcare Utilization Surveys	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.	From baseline to 5 years
The Median SHAQ Score	Scleroderma Health Assessment Questionnaire (SHAQ) is a self reported questionnaire with 8 domains including the following scales: pain, patient global assessment, vascular digital ulcers, lung involvement, and gastrointestinal involvement. The SHAQ is a quality of life measure. Each question is scored from 0 (defined as without difficulty), to 3 (defined as unable to do). Some domains are visual analog scales that are measured first and then changed to the 0-3 scale. The individual scores are combined and divided by 8. A higher score indicates worse functionality and changes in the SHAQ is measured as medium change from baseline. The reported medium change can range from -3 to 3. A negative medium change indicates a better outcome.	Baseline to year 4
The Number of Participants With Improvement in Pulmonary Function	Outcome measure was assessed as the number of participants who had greater than or equal to 3 months a > 10% improvement in predicted FVC or a > 15% improvement in DLCO.	From baseline to year 5
The Number of Participants With Significant Infectious Complications	Infections of grade 3 or above	Mobilization to Day + 100 post transplant
The Number of Participants With Non-progression Mortality	deaths without relapse of disease	Baseline to year 5
The Number of Participants Who Survived		Baseline to year 5
The Number of Participants Who Had Regimen-related Toxicities	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. The number of participants that experienced Grade 3 or higher adverse events is reported.	Baseline to 1 year post-transplant, grade 3 or higher adverse events
The Median Time of Initiation of Disease-modifying Antirheumatic Drugs (DMARDS) for Relapse After Transplant	The time in months from transplant to starting new therapy not MMF maintenance for relapse disease.	Transplant to year 5
Median Time to Treatment Failure	Time to treatment failure is defined as death or initiation of disease modifying antirheumatic drug (DMARD).	From transplant (day 0) to death or disease progression to year 5
The Number of Participants With Treatment-related Mortality	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.	Baseline to Day 90
The Number of Participants Who Completed ALL Work Productivity Survey (WPS)	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.	Baseline to year 5

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Leona Holmberg, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2011
• Primary Completion (Actual): September 15, 2023
• Study Completion (Actual): September 11, 2024

Study Registration Dates

• First Submitted: August 8, 2011
• First Submitted That Met QC Criteria: August 8, 2011
• First Posted (Estimated): August 10, 2011

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 12, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Connective Tissue Diseases; Skin Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antiviral Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adjuvants, Immunologic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-HIV Agents; Anti-Retroviral Agents; Lenograstim; Cyclophosphamide; Mycophenolic Acid; Antilymphocyte Serum; Thymoglobulin; Plerixafor
• Other Study ID Numbers: 2533.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); 2533; NCI-2011-01190 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RG1711052 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)