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Scleroderma Treatment With Autologous Transplant (STAT) Study

Information source: Fred Hutchinson Cancer Research Center
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Systemic Scleroderma

Intervention: peripheral blood stem cell transplantation (Procedure); cyclophosphamide (Drug); anti-thymocyte globulin (Biological); questionnaire administration (Other); laboratory biomarker analysis (Other); quality-of-life assessment (Procedure); filgrastim (Biological); autologous hematopoietic stem cell transplantation (Procedure); mycophenolate mofetil (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Official(s) and/or principal investigator(s):
George Georges, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Summary

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.

Clinical Details

Official title: A Phase II Multi-Center Study of High-Dose Cyclophosphamide and Antithymocyte Globulin Followed by Autologous Hematopoietic Cell Transplantation for the Treatment of Systemic Sclerosis

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: EFS of patients undergoing chemotherapy and transplant

Secondary outcome:

Overall survival

Non-relapse mortality (NRM)

Disease progression

Time to treatment failure

Improvement in pulmonary function

Improvement in pulmonary function

Improvement in pulmonary function

Improvement in pulmonary function

Improvement in pulmonary function

HRQOL

Change in renal function over time

Change in renal function over time

Change in renal function over time

Change in renal function over time

Change in cardiac function

Change in cardiac function

Change in cardiac function

Change in cardiac function

Change in cardiac function

Treatment-related mortality

All-cause mortality

Regimen-related toxicities

Infectious complications

Initiation of putative disease-modifying antirheumatic drugs (DMARDS) to modify disease

Health care utilization as assessed by UCSD Healthcare Utilization surveys

Work productivity Survey (WPS)

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 (uaing University of California San-Diego (UCSD) healthcare utilization.

OUTLINE:

STEM CELL MOBILIZATION AND PREPEARATION: 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) 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.

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

Eligibility

Minimum age: N/A. Maximum age: 69 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- GROUP 1:

- Patients must have 1) both a and b below; and 2) at least one of 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 < 45% of

predicted at the Clinical Review, (2) a hemoglobin-correct DLCO < 40% of predicted at the Baseline Screening visit, or (3) FVC < 45% of predicted at the Clinical review or 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 prior to randomization 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 at time of randomization

- 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 randomization, 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 randomization

- 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

Locations and Contacts

Colorado Blood Cancer Institute, Denver, Colorado 80218, United States; Recruiting
Richard Nash, Phone: 720-754-4800
Richard Nash, Principal Investigator

Boston University School of Medicine, Boston, Massachusetts 02118-2393, United States; Not yet recruiting
Vaishali Sanchorawala, Phone: 617-414-2507
Vaishali Sanchorawala, Principal Investigator

University of Michigan University Hospital, Ann Arbor, Michigan 48109, United States; Not yet recruiting
Daniel R. Couriel, Phone: 734-763-3110
Daniel R. Couriel, Principal Investigator

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
George E. Georges, Phone: 206-667-6886
George E. Georges, Principal Investigator

Additional Information

Starting date: September 2011
Last updated: January 24, 2013

Page last updated: February 07, 2013

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