Anti-CD38 Antibody Treating Evans Syndrome

Study Overview
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Brief Summary
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A single-center, open-label, off-label use investigator-initiated clinical study with safety run-in to explore the clinical activity and safety of Anti-CD38 Antibody in adult ES patients who have not responded adequately or relapsed after first-line treatment and at least one second-line therapy including immunosuppressive agents, Anti-CD20 Antibody and/or TPO-RA, or those in whom no other second-line treatment options are suitable.

Detailed Description
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Evans' syndrome (ES) is defined as the concomitant or sequential association of warm auto-immune haemolytic anaemia (AIHA) with immune thrombocytopenia (ITP), and less frequently autoimmune neutropenia. ES is a rare situation that represents up to 7% of AIHA and around 2% of ITP. Due to the rarity of the disease, the treatment of ES is mostly extrapolated from what is recommended for isolated auto-immune cytopenia (AIC) and mostly relies on corticosteroids, rituximab, splenectomy, and supportive therapies.Despite continuous progress in the management of AIC and a gradual increase in ES survival, the mortality due to ES remains higher than the ones of isolated AIC, supporting the need for an improvement in ES management. A branch of pathogenesis for ES has been revealed that plasma cells secrete pathogenic antibodies directed against platelet and red blood cell antigens. Antiplatelet specific plasma cells have been detected in the spleen of patients with rituximab refractory ITP. In those refractory cases, persistent autoreactive long-lived plasma cells in the bone marrow could explain treatment failure. Anti-CD38 antibody, such as Daratumumab, has been developed to target tumoral plasma cells in multiple myeloma, was recently found to be effective in antibody-mediated diseases, such as autoimmune cytopenia following hematopoietic stem cell transplantation, systemic lupus and also ES. This study will evaluate the safety and biologic activity of Anti-CD38 antibody in r/r primary ES who fail to respond to at least one previous second-line therapy or those who cannot chose suitable second-line therapy. The study will enroll approximately 10 participants. This trial will be conducted in China. All participants will be followed for at least 16 weeks after the 8 weeks of treatment.

Official Title
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A Prospective, One-arm and Open Clinical Study to Assess Safety and Efficacy of Anti-CD38 Antibody in the Treatment of Evans Syndrome

Conditions
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Evan Syndrome, Treatment

Intervention / Treatment
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* Drug: Anti-CD38 antibody Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥18 years. Prior to enrollment, a clinical diagnosis of primary Evans syndrome was made. Platelet count < 30×10^9/L or Hb < 100g/L or symptomatic anemia within 48 hours before the first administration of study drug; Failure to achieve response or relapse after corticosteroid therapy, and at least one second-line therapy or those who cannot chose other second-line therapy; If receiving emergency care for ES, treatment should be stopped >2 weeks before first dose. DAT positive (IgG+, with or without C3+). The patient need to be in the state of active hemolysis. With normal hepatic and renal functions. ECOG performance status ≤2. Cardiac function: New York Heart Association functional class ≤2. For patients receiving maintenance treatment, corticosteroids must have a stable dose at least 2 weeks before the first administration, TPO receptor agonists and azathioprine, danazol, cyclosporin A, tacrolimus, sirolimus, etc. must be stopped at least 4 weeks before the first administration; The end of anti-CD20 antibody treatment was>6 months.The end of alkylating agent treatment was>2 months. Understand the study procedures and voluntarily sign the informed consent form in person. Exclusion Criteria: Secondary Evans syndrome. Received any treatment of anti-CD38 antibody drug Uncontrollable primary diseases of important organs, such as malignant tumors, liver failure, heart failure, renal failure and other diseases; HIV positive; Accompanied by uncontrollable active infection, including hepatitis B, hepatitis C, cytomegalovirus, EB virus and syphilis positive; Accompanied by extensive and severe bleeding, such as hemoptysis, upper gastrointestinal hemorrhage, intracranial hemorrhage, etc.; At present, there are heart diseases, arrhythmias that need treatment or hypertension that researchers judge is poorly controlled; Patients with thrombotic diseases such as pulmonary embolism, thrombosis and atherosclerosis; Those who have received allogeneic stem cell transplantation or organ transplantation in the past; Patients with mental disorders who cannot normally obtain informed consent and conduct trials and follow-up; Patients whose toxic symptoms caused by pre-trial treatment have not disappeared; Other serious diseases that may limit the subject's participation in this test (such as diabetes; Severe cardiac insufficiency; Myocardial obstruction or unstable arrhythmia or unstable angina pectoris in recent 6 months; Gastric ulcer, etc.); Patients with septicemia or other irregular severe bleeding; Patients taking antiplatelet drugs at the same time; Pregnant women, suspected pregnancies (positive pregnancy test for human chorionic gonadotropin in urine at screening) and lactating patients.

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: Intervention（Anti-CD38 antibody）<br>10 enrolled subjects : once a week x 8 doses | Drug: Anti-CD38 antibody Injection<br>* intravenous Anti-CD38 antibody administration This study adopts a prospective, single arm, open design method. Ten subjects were enrolled in the study and were treated with Anti-CD38 antibody (16mg/kg/w) for 8 weeks. The first stage is the main research stage (d1-w8), which is the core treatment period. The subjects will receive intravenous infusion of 16mg/kg Anti-CD38 antibody once a week for 8 weeks to observe the safety and efficacy during treatment. The second stage (w9-w24) is the stage of withdrawal from the visit, mainly to observe the safety and continuous efficacy of Anti-CD38 antibody after treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of overall efficacy response after Anti-CD38 antibody treatment within 8 weeks | Overall response rate defined as improvement in any cytopenias by at least one grade, without worsening any other cytopenias or stable disease at least once within 8 weeks after the first dose. | 8 weeks | 
| Safety of Anti-CD38 antibody treatment | Incidence, severity, and relationship of treatment emergent adverse events after Anti-CD38 antibody treatment | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of stable sustained response after Anti-CD38 antibody treatment at week 8 | Stable sustained response rate defined as improvement in any cytopenias by at least one grade, without worsening any other cytopenias or stable disease in 3 consecutive accessible assessments at least 7 days apart 8 weeks after the first dose. | 8 weeks | 
| Number of Participants With ES Response to Anti-CD38 antibody treatment | Complete response (CR) is complete resolution in all autoimmune cytopenias (neutropenia, anemia thrombocytopenia) maintained for more than two months, combined with an ability to wean off corticosteroids and/or other immunosuppressive medication. Partial response (PR) is improvement in any cytopenias by at least one grade, lasting more than two months, without worsening any other cytopenias or stable disease with the ability to wean corticosteroids and/or immunosuppressive medications by at least 50%. No response (NR) is no change in cytopenias with treatment, and the inability to wean corticosteroids or other immunosuppressive medications. Progressive disease (PD) refers to obtaining a CR or PR by the 3 month observation and relapsing or progressing by the 6 month observation, leading to cessation of study drug. | 24 weeks | 
| Measurements of platelet count at each visit time point | Platelet count at each visit time point | 24 weeks | 
| Measurements of Hb value at each visit time point | Hb value at each visit time point | 24 weeks | 
| Measurements of hemolytic marker reticulocyte count at each visit time point | hemolytic marker reticulocyte count at each visit time point | 24 weeks | 
| Measurements of hemolytic marker LDH at each visit time point | hemolytic marker LDH at each visit time point | 24 weeks | 
| Measurements of hemolytic marker haptoglobin at each visit time point | hemolytic marker haptoglobin at each visit time point | 24 weeks | 
| Measurements of hemolytic marker total bilirubin at each visit time point | hemolytic marker total bilirubin at each visit time point | 24 weeks | 
| Emergency treatment | Percentage of subjects who received emergency treatment | 24 weeks | 
| Duration of platelet response | The longest duration for which the subject sustained a platelet count ≥50×109/L and at least 2-fold from baseline at the meanwhile | 24 weeks | 
| Duration of Hb response | The longest duration for which the subject sustained a Hb level ≥100 g/L, or a Hb level increased more than 20g/L than baseline | 24 weeks | 
| Reduction of concomitant drug | Percentage of patients with reduced doses of corticosteroids and/or other concomitant immunosuppressive drugs at baseline by 8 weeks of treatment | 8 weeks | 
| Number of subjects with clinically significant bleeding as assessed using the world health organization (WHO) bleeding scale | Changes of the subjects' numbers in WHO bleeding score after Anti-CD38 antibody treatment according to the reported World Health Organization's Bleeding Scale. The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss. | 24 weeks | 
| Assessment of fatigue function in chronic disease treatment | The scores of Functional Assessment of Fatigue in Chronic Illness Therapy (FACIT-F) before and after Anti-CD38 antibody treatment | 24 weeks | 
| Health status survey | The change of Health status Questionnaire (SF-36) score before and after Anti-CD38 antibody treatment | 24 weeks |