Efficacy of Anti-CD20 Ab Associated With Anti-CD38 in the Childhood Multidrug Dependent and Resistant Nephrotic Syndrome

NCT ID: NCT05704400

Last Updated: 2023-10-31

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-01
• Study Completion Date: 2025-03-01

Brief Summary

Nephrotic syndrome is considered a disease caused by an interplay of immunological stimuli with adaptive immunity(CD80/CD40) as trigger and Treg in the mid between co-stimulatory molecules and effectors. The positive effect of drugs blocking CD20 maturation in SDNS suggests a main role of these cells in regulating the system. Multidrug dependent, multidrug resistant nephrotic syndrome as well as post transplant FSGS recurrence patients can be considered difficult to treat patients and the association of two drugs, one targeting CD20 and a targeting plasmacells can be use in order to block the stimulatory cascade at more sites.

Detailed Description

Nephrotic syndrome is considered a disease caused by an interplay of immunological stimuli with adaptive immunity(CD80/CD40) as trigger and Treg in the mid between co-stimulatory molecules and effectors. The positive effect of drugs blocking CD20 maturation in SDNS suggests a main role of these cells in regulating the system. One possible explanation of proteinuria resolution by anti-CD 20 in most but not all patients with SDNS/MDNS is that some CD20 cells may escape the inhibition and mature in some cases to plasmacells. On this basis, it seems reasonable to consider the association of two drugs, one targeting CD20 and one targeting plasmacells in order to block the stimulatory cascade at more sites. There are recent positive evidences from the association of 2 monoclonal antibodies that block maturation of CD20 at different steps. One study utilized the humanized anti-CD20 antibody obinutuzumab(single dose 1,000 mg 1.73m2) in combination with the anti-CD38 (plasmacells) monoclonal antibody daratumumab (1,000 mg 1.73m2)18 in patients who relapsed after conventional treatments with Prednisone, rituximab and CNI and developed dependence to the combination of more than 2 drugs (MDNS). A cohort of 14 patients treated with the above association were included in a retrospective analysis: all of them suspended oral drugs, 5 out of 14 presented recurrence of proteinuria after about 10 months, 9 out of 14 were in stable remission after 20 months. Therefore, the use of 2 monoclonal antibodies in low doses is potentially valuable considering the positive results and also taking in account the safety of the treatment. While it is not possible to discern the separate effects of obinutuzumab and daratumumab when given together, the preliminary positive results of their combination may open new ways in the treatment of nephrotic syndrome and supports the necessity of new studies in those patients who require more than one drug to maintain remission. The investigators hypothesize that rituximab in place of obinutuzumab (not available in Italy for the use in nephrotic syndrome) with daratumumab could produce the same positive effects in MDNS and MRNS.

The Dual 1 is a before-after clinical trial testing the superiority of rituximab plus daratumumab in maintaining drug free disease remission in patients with multi-drug dependent nephrotic syndrome.

Conditions

Nephrotic Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

single arm

Group Type: EXPERIMENTAL

Rituximab Biosimilar ABP 798

Intervention Type: DRUG

Rituximab IV: the dose is standard for pediatric nephrotic syndrome; for dosage between 100 and 250 mg rituximab will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg rituximab will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg rituximab will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.

Daratumumab

Intervention Type: DRUG

Daratumumab vials 20 mg 1 ml will be collected to reach the desired dose of 16 mg /Kg, the dose is standard recommend to treat myeloma; diluted in 1000 ml of normal saline and infused at the constant speed of 50 ml/h. This will be reduced in case of cutaneous allergic reactions

Interventions

Rituximab Biosimilar ABP 798

Rituximab IV: the dose is standard for pediatric nephrotic syndrome; for dosage between 100 and 250 mg rituximab will be diluted in 100 ml of normal saline and administered at 2 ml/h for the first 30'; 3 ml/h for the second 30'; 6 ml/h for the third 30'; 15 ml/h until the end. For dosage between 260 and 500 mg rituximab will be diluted in 250 ml of normal saline and administered at 6 ml/h for the first 30'; 9 ml/h for the second 30'; 18 ml/h for the third 30'; 36 ml/h until the end. For dosage between 510 and 1000 mg rituximab will be diluted in 500 ml of normal saline and administered at 9 ml/h for the first 30'; thereafter, the infusion rate can be doubled every 30 minutes up to a maximum of 72 ml/h.

Intervention Type: DRUG

Daratumumab

Daratumumab vials 20 mg 1 ml will be collected to reach the desired dose of 16 mg /Kg, the dose is standard recommend to treat myeloma; diluted in 1000 ml of normal saline and infused at the constant speed of 50 ml/h. This will be reduced in case of cutaneous allergic reactions

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age between 3 and 24 years
• Multidrug dependent or resistant nephrotic syndrome for at least six months before enrolment. The need of at least 2 of the oral drugs listed below defines multidrug-dependence: prednisone at any doses, MMF 1200 mg m2 and CNI 0.1 mg day given in two doses. Dependence is defined by two consecutive relapses during double therapies or within 14 days of ceasing one of the three components of the therapeutic approach. Resistance is defined as lack of antiproteinuric effect of a double therapy based on steroid plusCNI or mofetilmycophenolate (MMF).Steroid resistance is defined by failure to achieve complete remission after 6 weeks with prednisone60 mg/m2.
• Post transplant recurrence of FSGS.
• Ability to provide consent and assent: parents'/guardian's written informed consent, and child's assent given before any study-related procedure not part of the subject's normal medical care, with the understanding that consent may be withdrawn by the subject any time without prejudice to his or her future medical care.

Exclusion Criteria

• Positivity to autoimmunity tests (ANA, nDNA, ANCA)
• Reduction of C3 levels.
• eGFR<60/ml/min/1,73 m2 valuated according to revised Bedside Schwartz Formula for patients between 2 and 17 years and with CKD-EPI Creatinine 2009 Equation for 18 years old patients.
• Pregnancy
• Neoplasm
• Infections: previous or actual HBV (with HBeAb positivity) or HCV infection
• CD20 B lymphocytes count <2,5%
• Treatment with Rituximab or cyclophosphamide in the last 6 months

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 24 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Istituto Giannina Gaslini

OTHER

Sponsor Role: lead

Responsible Party

Gian Marco Ghiggeri MD, PhD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gianmarco Ghiggeri, MD

Role: PRINCIPAL_INVESTIGATOR

IRCCS G. Gaslini

Locations

IRCCS G. Gaslini

Genova, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Gianmarco Ghiggeri, MD

Role: CONTACT

gmarcoghiggeri@gaslini.org

+39010-56363523

Andrea Angeletti, MD, PhD

Role: CONTACT

andreaangeletti@gaslini.org

+39010-56363523

Facility Contacts

GianMarco Ghiggeri, MD

Role: primary

References

Angeletti A, Bruschi M, Kajana X, La Porta E, Spinelli S, Caridi G, Lugani F, Verrina EE, Ghiggeri GM. Biologics in steroid resistant nephrotic syndrome in childhood: review and new hypothesis-driven treatment. Front Immunol. 2023 Aug 29;14:1213203. doi: 10.3389/fimmu.2023.1213203. eCollection 2023.

Reference Type: DERIVED

PMID: 37705972 (View on PubMed)

Other Identifiers

DUAL1

Identifier Type: -

Identifier Source: org_study_id