Anti-CD38 Antibody Treating Pediatric 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 Pediatric Primary Immune Thrombocytopenia

To evaluate the safety and efficacy of Anti-CD38 Antibody in the treatment of pediatric primary immune thrombocytopenia in patients who have not responded adequately or relapsed after first-line treatment and at least one second-line therapy including Anti-CD20 Antibody and/or TPO-RA, or those in whom no other second-line treatment options are suitable.

Study Overview

• Status: Recruiting
• Conditions: Immune Thrombocytopenia; Treatment
• Intervention / Treatment: Drug: Anti-CD38 antibody Injection

Detailed Description

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.

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 similar CD38 monoclonal antibody drugs, such as daratumumab, in the treatment of autoimmune diseases, including membranous nephropathy, systemic lupus erythematosus (SLE) and ITP, are also being carried out simultaneously. We 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 CD38 monoclonal antibody in the treatment of pediatric immune thrombocytopenia in patients who are steroid-refractory or steroid-dependent, and fail to respond to at least one previous second-line therapy, including Anti-CD20 Antibody and/ or TPO agonist.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yunfei Chen, MD; Phone Number: +8618502220788; Email: chenyunfei@ihcams.ac.cn
• Study Contact Backup: Name: Ting Sun, MD; Phone Number: +8615822339131; Email: sunting@ihcams.ac.cn

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Chinese Academy of Medical Science and Blood Disease Hospital
      • Contact: Yunfei Chen, MD; Phone Number: +86-22-23909009; Email: chenyunfei@ihcams.ac.cn
      • Contact: Ting Sun, MD; Phone Number: +86-22-23909009; Email: sunting@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 12-17 years old, male or female
• Conform to the diagnostic criteria of immune Thrombocytopenia (ITP)
• Diagnosis of ITP ≥3 months, and with a platelet count of <30 X 109/L measured within 2 days prior to inclusion
• Failure to achieve response or relapse after corticosteroid therapy, and at least one second-line therapy including rituximab or TPORAs.
• The previous emergency treatment of ITP (e.g. methylprednisolone, platelet transfusion, IVIG transfusion) must be completed at least 2 weeks before the first administration
• Signed and dated written informed consent
• With normal hepatic and renal functions
• ECOG physical state score ≤ 2 points
• Cardiac function of the New York Society of Cardiac Function ≤ 2
• Patients receiving maintenance treatment (including corticosteroids (less than or equal to 0.5mg/kg prednisone), TPO receptor agonists, etc.) must have a stable dose at least 4 weeks before the first administration, and azathioprine, danazol, cyclosporin A, tacrolimus, sirolimus, etc. must be stopped at least 4 weeks before the first administration; The end of rituximab treatment was>3 months；More than 6 months after splenectomy.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental: Intervention (Anti-CD38 antibody); 20 enrolled subjects : once a week x 8 doses

Drug: Anti-CD38 antibody Injection; intravenous Anti-CD38 antibody administration This study adopts a prospective, single arm, open design method. Twenty 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of Anti-CD38 antibody treatment	Incidence, severity, and relationship of treatment emergent adverse events after Anti-CD38 antibody treatment	24 weeks
Evaluation of overall efficacy response after Anti-CD38 antibody treatment within 8 weeks	Proportion of subjects with a platelet count ≥ 50 × 10^9/L within 8 weeks after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other efficacy evaluation	Including: 1. Proportion of subjects with a platelet count ≥ 50 × 10^9/L at week 2, week 4, week 6，week 8，week 10 and week 12 in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period; 2. Proportion of subjects achieving platelet counts ≥ 50×10^9/L at least once in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the first 12 weeks; 3. Proportion of subjects whose platelet counts ≥ 30×10^9/L and at least two times of baseline platelet count in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids within 8 weeks（two consecutive measurements at least 7 days apart）.	12 weeks
Duration from treatment initiation to platelet count ≥30×10^9/L and ≥50×10^9/L	Duration from treatment initiation to platelet count ≥30×10^9/L and ≥50×10^9/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids	12 weeks
Cumulative weeks of platelet ≥30×10^9/L and platelet ≥50×10^9/L	Cumulative weeks of platelet ≥30×10^9/L and platelet ≥50×10^9/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids	24 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
Reduction of concomitant drug	Percentage of patients with reduced doses of corticosteroids and/or other concomitant immunosuppressive drugs at baseline by 24 weeks of Anti-CD38 antibody treatment	24 weeks
Number of subjects with clinically significant bleeding as assessed using the bleeding scale for pediatric patients with ITP	Changes of the subjects' numbers in bleeding score after Anti-CD38 antibody treatment according to the reported bleeding scale for pediatric patients with ITP. The bleeding scale for pediatric patients with ITP is a measure of bleeding severity with the following grades: Grade 1 (minor) Minor bleeding, few petechiae (≤100 total) and/or ≤5 small bruises (≤3 cm in diameter), no mucosal bleeding；Grade 2 (mild) Mild bleeding, many petechiae (>100 total) and/or >5 large bruises (>3 cm in diameter), no mucosal bleeding；Grade 3 (moderate) Moderate bleeding, overt mucosal bleeding, troublesome lifestyle；Grade 4 (severe) Severe bleeding, mucosal bleeding leading to decrease in Hb>2 g/dL or suspected internal hemorrhage；	24 weeks
Measurements of platelet glycoprotein (GP) autoantibodies	level of anti-GPIIb/IIIa and Ib/IX antibodies before and after Anti-CD38 antibody treatment	24 weeks
Measurements of immunoglobulin quantification	The level of IgG, IgA, IgM and IgE quantification before and after Anti-CD38 antibody treatment	24 weeks
Measurements of various subsets of immunocompetent cells	To assess the changes of the percentage of B cell subsets，regulatory B cells（Breg），regulatory T cells (Treg)，supressor T cells（Ts），monocyte subcets, helper T cells（Th）subsets and the functionally-polarized CD4+ T cell subsets, etc. in peripheral blood mononuclear cells（PBMCs）before and after Anti-CD38 antibody treatment, and to compare with the healthy controls.	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic model establishment using multi-omics data such as transcriptome, proteome, metabolome, microbiome, et al.	The prognosis related factors will be selected from multi-omics data such as transcriptome, proteome, metabolome, microbiome, et al. And then selected prognosis related factors will be used to establish prognosis prediction model	24 weeks

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Lei Zhang, MD, Chinese Academy of Medical Science and Blood Disease Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: December 5, 2023
• First Submitted That Met QC Criteria: December 5, 2023
• First Posted (Actual): December 13, 2023

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Hematologic Diseases; Hemorrhage; Hemorrhagic Disorders; Blood Coagulation Disorders; Skin Manifestations; Blood Platelet Disorders; Thrombotic Microangiopathies; Purpura, Thrombocytopenic; Purpura; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Physiological Effects of Drugs; Immunologic Factors; Antibodies
• Other Study ID Numbers: CD38PEDITP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Researchers qualified can request the dataset, including de-identified individual subject data. Data may be requested from PI from 12 months 36 months after study completion.
• IPD Sharing Time Frame: 12 months to 36 months after study completion
• IPD Sharing Access Criteria: Upon request to PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No