Brentuximab Vedotin in Early Diffuse Cutaneous Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to assess feasibility, safety and preliminary efficacy of Brentuximab vedotin (Adcetris), a CD30-directed antibody-drug conjugate, in the treatment of active diffuse cutaneous systemic sclerosis (dcSSc).

Detailed Description
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Systemic sclerosis (SSc, Scleroderma) is a multisystem autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. Internal organ involvement results in increased mortality of SSc patients. There is no effective treatment for the majority of patients with early active diffuse scleroderma (diffuse cutaneous systemic sclerosis; dcSSc). These patients early in their disease may be able to reverse their inflammation and reduce the probability of irreversible fibrosis via significant immune modulation. This is a pilot study that will treat 10 patients with early or active dcSSc who meet inclusion criteria to determine if the benefit of Brentuximab vedotin and safety are favorable in order to consider a randomized controlled trial. This is a Phase II study that is uncontrolled and patients will remain on their background immune suppressive treatment unless if contraindicated for safety or drug interactions. The trial is powered to show a mean change in mRSS of 8 over one year in an uncontrolled, unblinded study. The Health Assessment Questionnaire Disability Index (HAQ), patient and physician global scores, inflammatory markers (ESR, CRP), and combined response index in SSc (CRISS) will all be exploratory outcomes. Other outcomes such as changes in CD30-stained cells on skin biopsies with IHC from baseline to end of the trial will be explored if the study is positive.

Official Title
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A Pilot Study of Adcetris Treatment in Active Diffuse Cutaneous Systemic Sclerosis (Diffuse Scleroderma)

Conditions
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Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
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* Drug: Brentuximab Vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 18 years or older able to give informed consent meet the ACR/EULAR classification criteria for SSc early dcSSc (disease duration ≤ 5 years from first non-Raynaud's phenomenon symptom) OR active dcSSc as determined by worsening mRSS, presence of tendon friction rubs, and/or elevated inflammatory markers thought to be due to active dcSSc and not related to other issues mRSS≥ 15 a negative TB skin test at screening, or treatment with INH for 6 months or other standardized LBTI (latent TB infection) treatment in the past Exclusion Criteria: Poor pulmonary function (FVC<40% and/or DLCO<30%). Pregnancy, breast feeding or child bearing potential without practicing reliable contraception (and partners for men in the study). Clinically significant pulmonary hypertension requiring drug therapy. Clinically significant cardiac disease. Chronic or ongoing active infectious disease requiring systemic treatment. Seropositivity for human immunodeficiency virus (HIV) at study entry. Active tuberculosis (TB) infection. Active viral infection with viral replication of hepatitis B or C virus at study entry. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, pancreatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease; and cancer. Peripheral neuropathy at screening Grade 2 or higher. Known or suspected hypersensitivity to components of the treatment Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder) Any of the following laboratory abnormalities at screening: Absolute neutrophils count <2000/mm3 Hemoglobin <85 g/L Platelet count < 100,000/mm3 AST/SGOT or ALT/SGPT >2.0 UNL Participation in another clinical trial within six weeks before randomization in this study Use of rituximab within the previous 4 months. Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit. Previous use of brentuximab vedotin. Current or history of progressive multifocal leukoencephalopathy (PML).

Ages Eligible for Study
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Minimum 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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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of Brentuximab vedotin<br>Maximum duration of treatment: 48 weeks Maximum dose allowed: 0.6 mg/kg Route of administration: intravenous use | Drug: Brentuximab Vedotin<br>* Dose 0.6 mg/kg i.v. will be given every 3 weeks for 16 cycles (48 weeks) in addition to standard of care medications for SSc that may include cyclophosphamide, methotrexate, azathioprine, mycophenylate mofetil (MMF, cellcept) and mycophenolic acid (myfortic).<br>* Other names: ADCETRIS, SGN-35;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in skin thickness measured by modified Rodnan Skin Score (mRSS) |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mRSS |  | 3, 6 and 9 months | 
| CRISS score >20% |  | 6 months | 
| Change in FVC, % |  | 6 and 12 months | 
| Change in DLCO, % |  | 6 and 12 months | 
| Change in physician-assessed disease activity, severity and damage on VASs ranked from 0 to 10 |  | 3,6,9 and 12 months | 
| Change in patient global assessment of health status (VAS 0 to 10) |  | 3,6,9 and 12 months | 
| Change in Health Transition score |  | 3,6,9 and 12 months | 
| Change in SHAQ |  | 3,6,9 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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connective tissue diseases, skin diseases, immunologic factors, systemic sclerosis, scleroderma, brentuximab vedotin, CD30-directed antibody-drug conjugate, antirheumatic agents, antineoplastic agents