Phase 2a Study Evaluating the Arsenic Trioxide (ATO) in Systemic Lupus (SLE) (Protocol LUPSENIC)

Study Overview
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Brief Summary
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Primary objectives : To investigate the safety and the tolerability of ATO by IV infusions to patients with SLE, To determine the maximum tolerated dose of ATO. Secondary objectives : Evaluation of the clinical and biological response of the SLE to ATO, Time of relapse in case of positive response, Determination of the efficacy, Pharmacokinetic study of ATO.

Official Title
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Phase 2a Study Evaluating the Arsenic Trioxide (ATO) in Systemic Lupus (SLE)

Conditions
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Systemic Lupus

Intervention / Treatment
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* Drug: Arsenic trioxide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Systemic Lupus meeting the ACR (American College of Rheumatology) criteria, progressive either SLEDAI activity score ≥ 4, despite a corticosteroid therapy ≥ 10 mg / d associated with hydroxychloroquine (in the absence of contraindication or intolerance) and / or an immunosuppressive treatment at a stable dose, Insured, Availability for hospitalization required by the protocol (conventional and daily hospitalizations). Exclusion Criteria: Inability to give their signed informed consent form, Performans status > 2 QTcorrected space before treatment > 0.45 seconds Hemoglobin less than 11g/dL Neutrophils rate below 1 200 / mm3 Platelets rate below 100 Giga / mm3 Previous history of arrhythmia or heart rhythm disorder or other rhythm trouble by referring cardiologist Heart disorder (progressive pericarditis, valvular disease, ...) according to cardiologist Family previous history of arrhythmias Taking drugs that potentially prolong the QT Hypersensitivity to the active substance of Trisenox® or any of the excipients Serum potassium ≤ 4 milliequivalent / L Magnesemia ≤ 1,8 mg / dl Increase corticosteroids beyond 20 mg / day within 15 days before inclusion Immunosuppressive treatments, thalidomide introduced within the last 3 months Biotherapy (rituximab, belimumab, ...) introduced within 6 months prior to inclusion Pregnancy or lactation For women of childbearing age, men and their partner : unless effective contraception for the duration of participation in the study that is 7 months Creatinine clearance <50 ml / min, Hepatocellular insufficiency (TP <50%), and / or AST (aspartate aminotransferase) / ALT (alanine aminotransferase) / ALP (alkaline phosphatase) > 2N HBsAg positive, DNA detectable HbS Infection with HIV, HBV (hepatitis B virus) or HCV (hepatitis C virus) Renal or progressive central neurological impairment with possible alternative therapeutic (to be discussed with the principal investigator and scientific board meeting) Peripheral neuropathy Unweaned alcoholism Minor Patients older than 65 years Patient having been professionally exposed to arsenic (cleaning electronic circuits for example) Guardianship patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Arsenic trioxide<br>Thirteen patients will be successively included in this study at 6 different dose levels of arsenic trioxide (0.075, 0.10, 015, 0.20, 0.25 and 0.30 mg / kg / day). | Drug: Arsenic trioxide<br>* The study duration was 30 months (24 months recruitment + 6 months follow-up).Thirteen patients will be successively included in this study at 6 different dose levels of arsenic trioxide (0.075, 0.10, 015, 0.20, 0.25 and 0.30 mg / kg / day). The treatment should be administered by IV infusion over 2 hours of D1 to D4 (conventional hospitalization) and at D8, D11, D15, D18, D22 and D25. The protocol starts at the dose of 0.10 mg / kg / day. The stage at the dose of 0.075mg/kg/day is planned in case of toxicity with the first stage at the dose of 0.10mg/kg/day. The course of study is as follows : Pre-inclusion between D-35 and D-15 Ten injections during the first month distributed as follows : conventional hospitalization from D1 to D4 (one injection per day) and daily hospitalization day for injections at D8, D11, D15, D18, D22 and D25. A telephone contact between D32 and D34 A consultation at D40 then monthly consultation at D60, D90, D120, D150 and D180<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac adverse events whatever grade and any adverse event of grade 3 or 4 | The definition of toxicity will be based on Common Terminology Criteria for Adverse Events, version 4 of the U.S. Department of Health and Human Services, National Institutes of Health / National Cancer Institute. The investigators will consider the occurrence of a significant toxicity if at least one of the following events is observed : Any symptomatic toxicity (and / or abnormality) cardiac and / or QTc prolongation > 480 msec., Apart from cardiac toxicity, toxicity of any grade 3 or 4 and irreversible toxicity (within 30 days) of any grade 1 or 2. | 30 days after the last infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite response of SLE | Combined clinical response using the composite response of SLE or SRI (SLE Responder Index) (SLEDAI + BILAG (British Isles Lupus Assessment Group) + PGA) : a positive response is defined by a reduction of SELENA SLEDAI of at least 4 points, no worsening ( > 0,3 point) of the physician's global assessment (PGA), no new score A and no more than one new score B about BILAG. This composite index is now the benchmark tool for evaluating therapeutic protocols in SLE. | 30 months | 
| Anti-nuclear antibodies (ANA). | The modification of anti-nuclear antibodies (ANA). | 30 months | 
| Anti-native DNA | The modification of anti-native DNA. | 30 months | 
| C3 complement | The modification of C3 complement. | 30 monhs | 
| C4 complement | The modification of C4 complement. | 30 months | 
| Sedimentation rate | Analysis of Sedimentation rate. | 30 months | 
| Serum creatinine | Analysis of serum creatinine. | 30 months | 
| Proteinuria/creatinuria ratio | Analysis of proteinuria/creatinuria ratio. | 30 months | 
| Serum protein electrophoresis | Analysis of serum protein electrophoresis. | 30 months | 
| Quantitation of immunoglobulins | Analysis of quantitation of immunoglobulins. | 30 months | 
| Quality of life | Assessment of quality of life wih questionnaires SF36 and LupusQol. | 30 months | 
| Steroids | Reduction of the dose of steroids throughout the study. | 30 months | 
| Immunosuppressive treatments | Cessation of immunosuppressive treatments. | 30 months | 
| Response time | Response time in case of positive response. | 30 months | 
| Time to relapse | Time to relapse in case of positive response. | 30 months | 
| Blood test of arsenic | Pharmacokinetic study of arsenic plasma with analysis of potential correlations blood rates/ toxicity and response. | D1, D2, D3, D4, D8, D11, D15, D18, D22 and D25 (before and after each infusion) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arsenic trioxide, Systemic Lupus, clinically, biologically active