A Multicenter Phase 2 Single-arm Proof-of-concept Trial Assessing the Efficacy and Safety of Obinutuzumab in the Treatment of Non-infectious Active Cryoglobulinemia Vasculitis Refractory or Intolerant to Rituximab

Inclusion Criteria: 1. Age ≥ 18 years 2. Written informed consent 3. Active mixed cryoglobulinemia vasculitis defined by: * a clinically active vasculitis signs with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary * and/or cardiac involvement, * and history of positive cryoglobulinemia and/or positive Rheumatoid factor associated with low C4 complement level, and/or a monoclonal component (IgM Kappa) and/or a histological proof of vasculitis in the affected organs 4. Refractory or intolerant to Rituximab. Refractory patients are defined as any of the following after a standard rituximab regimen (375 mg/m² IV weekly for 4 consecutive weeks): * No measurable improvement within 4-6 weeks of initiation, * OR \<50% improvement in the number or severity of affected organ systems at 12 weeks, or * OR Persistent baseline manifestations without remission or significant improvement for \>12 weeks. Improvement: A measurable positive change in the clinical signs, symptoms, and/or functional status of the affected organ(s), compared to baseline, as assessed using the organ-specific criteria below, without fulfilling full remission requirements. Remission: Complete disappearance of all baseline symptoms and objective abnormalities in the affected organ(s), as defined below: "CRYOBI " protocol, version v1-2 of 26/08/2025 10/68 This document is the property of DRCI/AP-HP. All reproduction is strictly prohibited. Version 4.0 dated 31/05/2019 * The skin and articular remissions are evaluated clinically (disappearance of purpura and ulcers, disappearance of arthritis, disappearance of the skin necrosis). * Renal remission is evaluated biologically (proteinuria \<0.5g/24h or proteinuria/creatininuria \<50 mg/mmol), and improvement of GFR \>20% if GFR \<60 mL/min/1.73 m2 at diagnosis or glomerular filtration rate ≥60ml/min/1.73m² if GFR ≥ 60 mL/min1.73 m2 at diagnosis * Peripheral Neurological remission is evaluated clinically (any improvement of pains and paresthesia by visual analogue scales, any stabilization or improvement of muscular testing in case of motor impairment at baseline) and electrophysiologically (stabilization or improvement of electromyogram abnormalities compared to baseline). * Central Neurological remission is evaluated clinically (no new neurological symptoms and stabilization or improvement of the initial presentation) and radiologically (Cerebral MRI showing no new lesions and no contrast enhancement of the initial lesions, or regression of the initial lesion) * Digestive remission is evaluated clinically (resolution of abdominal pain and other gastrointestinal symptoms), and by endoscopy (resolution of potential gastrointestinal lesions seen at baseline) and/or by CT scan (resolution of any abnormalities found on baseline imaging). Complete remission of all baseline abnormalities is required to define digestive remission. * Cardiac remission is evaluated clinically (resolution of chest pains and other cardiac events), and biologically (normalization of myocardial enzymes) and radiologically (no late gadolinium enhancement on cardiac MRI). Complete remission of all baseline abnormalities is required to define cardiac remission. Pulmonary remission: complete regression of the initial symptoms with no new radiological lesions and regression of all the initial lesions. Intolerant: Patients who experienced treatment-limiting adverse events or toxicity that required discontinuation of rituximab, despite dose modification or supportive care. 5. HIV negative serology within 3 months prior inclusion 6. Negative HBs Ag test within 3 months prior inclusion. (In case of negative AgHBs and positive HBc Ab test, HBV DNA test must be negative; AND Hepatitis B surveillance should be started (monthly HBsAg and HBV DNA testing for the duration of the study treatment and at least every 12 weeks after treatment is discontinued for the duration of study treatment. In addition, antiviral prophylaxis should be started before the first administration of the study treatment and continued until 12 months after completion of study treatment) 7. HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion 8. Affiliated to National French social security system (registered or being a beneficiary of such a scheme). Patients with AME are eligible Exclusion Criteria: 1. Vasculitis unrelated to cryoglobulinemia 2. Non-active cryoglobulinemia vasculitis 3. Treatment with cyclophosphamide or Belimumab within 3 months prior to inclusion 4. Malignant neoplasm within the last 5 years other than carcinoma in situ of the cervix or excised basal cell, squamous cell carcinoma of the skin and low-grade hemopathy with no indication for a specific treatment. "CRYOBI " protocol, version v1-2 of 26/08/2025 11/68 This document is the property of DRCI/AP-HP. All reproduction is strictly prohibited. Version 4.0 dated 31/05/2019 Carcinoma in situ of the cervix and squamous cell carcinoma of the skin should have been adequately treated before inclusion in the study. 5. Active tuberculosis, pneumocystis, cytomegalovirus or any active infection not adequately managed or considered a risk by the investigator 6. Have a history of an anaphylactic reaction to parenteral administration of Obitunuzumab 7. Unstable or high-risk cardiac conditions, e.g., recent (\<6 months) myocardial infarction or unstable angina, decompensated (NYHA III-IV) heart failure, clinically significant uncontrolled arrhythmias, or any cardiac condition that, in the investigator's judgment, poses an unacceptable risk with obinutuzumab infusion 8. Pregnant or breastfeeding women, or desire to become pregnant within 30 months All women of childbearing potential (WOCBP) are required to have a negative pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using an eff