Campath-1h Phase I/II Pilot Trial as Immunoablative Therapy for Refractory Systemic Sclerosis

Study Overview
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Brief Summary
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This phase I/II pilot trial seeks to demonstrate that prolonged administration of Campath-1H without prior marrow or stem cell harvesting can result in immunoablation similar to that achieved by hematopoietic stem cell transplantation (HSCT) from either bone marrow or peripheral blood stem cell sources in children and adolescents with severe treatment refractory systemic sclerosis (SSc).

Detailed Description
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Patients, 8 to18 years of age, will be included if they have a proven diagnosis of diffuse cutaneous or systemic SSc as defined by the ACR criteria with evidence of active inflammatory disease Plus at least 1 of the following:SSc-related pulmonary disease with forced vital capacity (FVC) or hemoglobin-adjusted DLCO < 70% and evidence of alveolitis by high-resolution CT scan or bronchoalveolar lavage. OR:History of SSc-related renal crisis or disease, not active at the time of screening OR:Moderate to severe upper and/or lower gastrointestinal involvement AND:Unacceptable toxicity or steroid dependence > 0.3 mg/kg/d, OR:Failure to respond to, or unacceptable toxicity of MTX > 1mg/kg in combination with cyclosporine or azathioprine or cyclophosphamide 2 kg/d or Rituximab 375 mg/m2 x 4 doses or Imatinib 800 mg/ OR:Disease recurrence after tapering medication above

Official Title
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Campath-1h as Immunoablative Therapy for Children and Adolescents With Treatment Refractory Systemic Sclerosis

Conditions
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Scleroderma

Intervention / Treatment
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* Drug: Campath


Participation Criteria
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Eligibility Criteria
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4.2 Inclusion/Exclusion criteria 4.2.1 Inclusion criteria 8 to 21 years of age, inclusive Diffuse, cutaneous dcSSc as defined by the ACR criteria with evidence of active inflammatory disease. Plus at least 1 of the following: dcSSc-related pulmonary disease with forced vital capacity (FVC) or hemoglobin-adjusted DLCO < 70% and evidence of alveolitis by high-resolution CT scan or bronchoalveolar lavage OR o History of SSc-related renal crisis or disease, not active at the time of screening OR Moderate to severe upper and/or lower gastrointestinal involvement AND Unacceptable toxicity or steroid dependence > 0.3 mg/kg/d Failure to respond to, or unacceptable toxicity of MTX > 1mg/kg in combination with cyclosporine or azathioprine or cyclophosphamide or Rituximab 375 mg/m2 x 4 doses or Imatinib 800 mg/d or tocilizumab 8 mg/kg for at least 3 doses. Disease recurrence after tapering medication above (in #4) 4.2.2 Exclusion Criteria Pulmonary, cardiac, hepatic, or renal impairment that would limit therapy and compromise survival includes, but is not restricted to, any of the following: Severe pulmonary dysfunction: hemoglobin-corrected DLCO < 45%, DLCO <4 mL/mmHg/min/L or pO2 < 70 mm Hg or pCO2, ≥ 45 mm Hg without supplemental O2 sat 92% at rest without supplemental O2 Significant pulmonary hypertension Uncontrolled clinically significant arrhythmias NYHA heart failure class IV LVEF < 50% by echo or prior insertion of a pacemaker or cardioverter-defibrillator End-stage renal disease (GFR<50 ml/min/1.73 m2 or creatinine . 2 mg/dl; estimated CrCl < 40 mL/min or active, untreated dcSSc renal crisis at time of enrollment Active hepatitis (ALT, AST, or bilirubin > 2x ULN) Active gastric antral vascular ectasia (GAVE, watermelon stomach) 2 mg/kg/day prednisone or equivalent within 30 days of treatment Unwilling or unable to discontinue DMARDs for treatment of dcSSc Co-morbid illnesses with an estimated median life expectancy < 5 Years Active uncontrolled infection Positive serology for hepatitis B or C, HIV ANC < 1500 cells/µL, platelets < 120,000 cells/µL, Hct < 27% or Hgb < 9.0 g/dL Malignancy within the previous 2 years, excluding treated skin cancer Myelodysplasia Uncontrolled hypertension History of hypersensitivity to murine or E. coli proteins Pregnancy or unwilling to use contraceptive methods for at least 15 months Steroid dependence: > 2mg/kg/day, prednisone or equivalent within 30 days prior to treatment History of substance abuse within the last 5 years History or presence of 2nd autoimmune disease requiring immunosuppressive therapy that has a substantial risk of recurrence Demonstrated lack of compliance with prior medical care Lack of rehabilitation potential 4.3 SSc patients, who fulfill the inclusion criteria, will then be assessed for residual thymic function since our previous study of pediatric dcSSc patients demonstrated that the dcSSc patients had decreased thymic function as compared to age matched controls as measured by the proportion of naïve CD4+ T lymphocytes (CD4+, CD31+), recent thymic emigrants (RTE). (5) Patients with less than 40% RTE will be excluded because of concerns about their ability to reconstitute their immune system after immune ablation. 4.4 dcSSc patients, who fulfill the screening criteria, will be consented for entry into the clinical trial.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 18 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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Campath|Pediatric patients with dcSSc are eligible for the clinical trial if they fulfill the inclusion and exclusion criteria of the trial. The inclusion and exclusion criteria are based upon those of the SCOT trial for adult dcSSc patients, which is the Phase 3 clinical trial in the United States comparing autologous HSCT to monthly high dose cyclophosphamide (CY) alone.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome | To determine why the extended administration of Campath-1H results in immune ablation in some patients and immunosuppression in others, Number of Participants with Adverse Events as a Measure of Safety and Tolerability Campath-1H antibody levels during and after the completion of the Campath administration. (47) Thus, both the peak Campath-1H levels as well as the duration of circulating Campath will be determined. | 2 years | 
| Campath | Number of Participants with Adverse Events as a Measure of Safety and Tolerability | The site will follow patients for 6 months post adverse event. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Patients with Scleroderma