Anti-CD38 Antibody Treating Children With Primary Immune Thrombocytopenia (ITP)

A Prospective, One-arm and Open Clinical Study to Assess Safety and Efficacy of Anti-CD38 Antibody in the Treatment of Children With Primary Immune Thrombocytopenia

To evaluate the safety and efficacy of Anti-CD38 Antibody in the treatment of primary immune thrombocytopenia in patients who have failed first-line treatment.

Immune thrombocytopenia (ITP) is an organ-specific autoimmune disease, which is characterized by decreased platelet count and skin and mucosal bleeding. ITP is a kind of disease with increased platelet destruction and impaired platelet production caused by autoimmunity. Conventional treatment of adult ITP includes first-line glucocorticoid and immunoglobulin therapy, second line TPO and TPO receptor agonist, splenectomy and other immunosuppressive treatments (such as rituximab, vincristine, azathioprine, etc.). ITP is one of the most common hemorrhagic diseases. At present, the treatment response of ITP is not good, and a considerable number of patients need drug maintenance treatment, which seriously affects the quality of life of patients and increases the economic burden of patients. Therefore, there is still a lack of effective treatment for adult ITP, especially for recurrent and refractory ITP patients, which is one of the problems that have attracted more attention and need to be solved urgently.

The main pathogenesis of ITP is the loss of platelet autoantigen immune tolerance, which leads to abnormal activation of humoral and cellular immunity. It is characterized by antibody mediated platelet destruction and insufficient platelet production by megakaryocytes. The residual long-term autoreactive plasma cells may be a source of therapeutic resistance to autoimmune cytopenia. Antiplatelet specific plasma cells have been detected in the spleen of patients with rituximab refractory ITP. Therefore, the strategy of simply eliminating B cells may not work, because LLPC will continue to produce pathogenic antibodies. However, targeting LLPC becomes a new strategy to treat autoimmune diseases.

Daratumumab, a kind of anti-CD38 antibody, is a new type of monoclonal antibody targeting CD38. It targets plasma cells and has carried out some clinical studies in multiple myeloma, with good therapeutic effects. In addition, the clinical trials of daratumumab in the treatment of autoimmune diseases, including membranous nephropathy, systemic lupus erythematosus (SLE) and ITP, are also being carried out simultaneously. The investigators assume that autologous reaction LLPC may be the cause of treatment failure in some ITP patients. Therefore, the use of CD38 monoclonal antibody to clear long-term surviving plasma cells in ITP patients may be a new strategy for treating ITP patients.

Therefore, the investigators designed this clinical trial to evaluate the safety and efficacy of daratumumab in the treatment of immune thrombocytopenia in patients who are steroid-refractory or steroid-dependent.

Inclusion Criteria:

• Age ≥6 years, ≤18 years, male or female.
• Before enrollment, the subjects have been clinically diagnosed with primary immune thrombocytopenia for no less than three months according to the American Society of Hematology guidelines 2011 Evidence-Based Practice Guideline (Neunert et al. 2011) or the International Consensus Report for the Investigation and Management of Primary Immune Thrombocytopenia (Provan et al. 2010), as applicable locally.
• Patients have failed glucocorticoid therapy (either due to inefficacy, efficacy could not be maintained, or relapse). Patients should have a history of response to previous ITP standard first-line therapy (glucocorticoids and/or intravenous human immunoglobulin) (PLT≥50×10^9/L);
• Platelet count <30×10^9/L within 24 hours before the first administration of the study drug; During the screening period, platelet counts were measured at least 2 times (at least 1 week apart), with an average platelet count <30×10^9/L and no platelet count > 35×10^9/L.
• ECOG performance status score of ≤2.
• Enrollment of subjects receiving maintenance therapy is permitted, including glucocorticoids (≤0.5 mg/kg of prednisone or equivalent) or TPO receptor agonists. Only one concomitant medication was allowed at the time of enrollment, and the concomitant medication must have been stable for a minimum of 4 weeks prior to the first dose of the study drug.
• For fertile female patients, a negative pregnancy test result is required. Fertile female and male patients must use effective contraception separately during the study and for 4/6 months after the cessation of study drug treatment.
• Subjects comprehensively understand and can adhere to the study protocol requirements and willingly signed the informed consent form.

Exclusion Criteria:

• Those who are allergic to anti-CD38 monoclonal antibody or excipients, or who have received anti-CD38 monoclonal antibody in the past and failed or kept a continuous response of less than 6 months.

• All kinds of secondary thrombocytopenia or autoimmune hemolytic anemia.

• Any history of thrombotic or embolic events or extensive and severe bleeding, such as hemoptysis, massive upper digestive tract hemorrhage, intracranial hemorrhage, etc., or sepsis or other irregular bleeding within 12 months before the first medication.

• Participated in or was exposed to any other investigational drug study (including vaccine study) during the 4 weeks or 5 half-lives (whichever is older) prior to the first dose.

• Patients taking antiplatelet drugs within 3 weeks before the first dose.

• Subjects who have received emergency treatment for ITP (e.g., methylprednisolone, platelet transfusion, intravenous immunoglobulin infusion, or thrombopoietin receptor agonist therapy) within 2 weeks prior to the first dose of study drug.

• Subjects who have been treated with medications including azathioprine, danazol, dapsone, cyclosporine A, tacrolimus, and sirolimus within 4 weeks prior to the first dose of study drug. Subjects who have receive anti-CD20 monoclonal antibodies such as rituximab, or medications including cyclophosphamide and vindesine within 6 months prior to the first dose of study drug.

• Subjects who have undergone splenectomy within 6 months prior to the first dose of study drug.

• Subjects who have received live vaccines within 4 weeks prior to the first dose of study drug, or plan to receive any live vaccines during the course of the study.

• Subjects who are diagnosed with Myelodysplastic syndromes (MDS); Subjects with a with a history of malignancy within the 5 years prior to screening (excluding completely cured in situ cervical cancer and non-metastatic skin squamous cell carcinoma or basal cell carcinoma).

• Subjects who have undergone allogeneic stem cell transplantation or organ transplantation.

• Subjects with a clinically significant medical history, as perceived by investigators, that will pose risks to subjects' safety during the study or potentially affect the safety or efficacy analyses, includes major clinical histories such as circulatory system abnormalities, endocrine system abnormalities, nervous system diseases, blood system diseases, immune system diseases, mental diseases and metabolic abnormalities and so on. e.g., subjects with acute myocardial infarction, unstable angina pectoris, or severe arrhythmias (multifocal ventricular premature contractions, ventricular tachycardia, or ventricular fibrillation) within the 6 months before screening ; New York Heart Association (NYHA) class III-IV heart failure; subjects who were known to have had moderate or severe persistent asthma or chronic obstructive pulmonary disease within the 5 years prior to screening, or whose condition was currently poorly controlled;

• Subjects with a history of severe recurrent or chronic infections, or acute infections requiring systemic treatment with antibiotics, antiviral drugs, antiparasitic drugs, anti-amoebic drugs, or antifungal drugs within 4 weeks prior to the first dose and during the screening period, or superficial skin infections requiring systemic treatment within one week prior to the first dose of study drug. Notably, after the resolution of the infection, the subject may be re-screened.

• Subjects with a history of known or suspected immunosuppression, including invasive opportunistic infections such as histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis pneumonia, and aspergillosis, even if the infection has resolved; or unusually frequent, recurrent, or prolonged infections (as judged by the investigator).

• Significant laboratory abnormalities during screening included:

  1. Alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal (ULN).
  2. Total bilirubin greater than 1.5 times the ULN (note: subjects diagnosed with Gilbert syndrome based on medical records should not be excluded based on this criterion).
  3. absolute neutrophil count < 1500/mm3.
  4. hemoglobin < 9g/dL; IgG < 500 mg/dL.
  5. lymphocyte count < 500/mm3.
  6. Creatinine clearance (CrCl) < 30 mL/min (i.e., CrCl ≥30 mL/min is allowed)

• Positive for HIV antibodies or syphilis antibodies.

• Subjects test positive for Hepatitis B surface antigen (HBsAg) or subjects test positive for hepatitis B core antibody and HBV-DNA (through polymerase chain reaction testing), or subjects test positive for hepatitis C virus antibody and HCV-RNA during the screening period. Subjects with positive hepatitis B core antibody but negative HBV-DNA can be enrolled, with HBV-DNA monitoring every 4 weeks.

• Pregnant or lactating women, or those intending to conceive or breastfeed during the study; and male partners intending to induce pregnancy during the study.

• Any other conditions unsuitable for participation in this study, as assessed by the investigator.