Scleroderma Treatment With Autologous Transplant (STAT) Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Systemic Scleroderma

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (HDIT autologous PBSCT)<br>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. | Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: Thymoglobulin;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Autologous Stem Cell Transplantation;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Drug: Plerixafor<br>* Given SC<br>* Other names: SDZ SID 791;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS of patients undergoing chemotherapy and transplant | 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. | At 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | Defined as any death. | Assessed up to 5 years | 
| Change in cardiac function | Measured by ejection fraction on echocardiogram (percentage). | Year 1 | 
| Change in cardiac function | Measured by ejection fraction on echocardiogram (percentage). | Year 2 | 
| Change in cardiac function | Measured by ejection fraction on echocardiogram (percentage). | Year 3 | 
| Change in cardiac function | Measured by ejection fraction on echocardiogram (percentage). | Year 4 | 
| Change in cardiac function | Measured by ejection fraction on echocardiogram (percentage). | Year 5 | 
| Change in renal function over time | Measured by serum creatinine. | Baseline | 
| Change in renal function over time | Measured by serum creatinine. | Week 12 | 
| Change in renal function over time | Measured by serum creatinine. | Week 26 | 
| Change in renal function over time | Measured by serum creatinine. | Annually for 5 years | 
| Disease progression |  | 6 months and then annually for 5 years | 
| 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. | Assessed up to 5 years | 
| HRQOL as measured by the PROMIS-29 version 1.0 |  | Annually for 5 years | 
| HRQOL as measured by the SF-36 |  | Annually for 5 years | 
| HRQOL as measured by the SGRQ |  | Annually for 5 years | 
| HRQOL as measured by the SHAQ |  | Annually for 5 years | 
| Improvement in pulmonary function | 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. | Baseline | 
| Improvement in pulmonary function | 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. | 1 month | 
| Improvement in pulmonary function | 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. | Week 12 | 
| Improvement in pulmonary function | 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. | Week 26 | 
| Improvement in pulmonary function | 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. | Annually for 5 years | 
| Infectious complications |  | Assessed up to 5 years | 
| Non-progression mortality |  | Assessed up to 5 years | 
| Overall survival |  | Assessed up to 5 years | 
| 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. | Up to 1 year post-transplant | 
| Time of initiation of putative disease-modifying antirheumatic drugs (DMARDS) to modify disease | A decision to initiate disease-modifying therapy other than that specified in the protocol will be considered as an indication of disease progression or activity and thus fulfills this secondary endpoint. In general, this would include the administration of any therapy (drugs, biologics, or any other treatments) clearly given for the purpose of treating the underlying SSc. This will include any Food and Drug Administration-approved agents and experimental agents not currently available but that become available during the period of the trial. | After transplant, up to 5 years | 
| Time to treatment failure |  | 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 | 
| 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. | Day 90 | 
| 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. | Assessed up to 5 years |