Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome

NCT ID: NCT03383380

Last Updated: 2024-07-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-01
• Study Completion Date: 2023-11-30

Brief Summary

The purpose of this proposed research is to evaluate the efficacy and safety of the rapamycin therapy in patients with activated phosphoinositide 3-kinase δ syndrome (APDS).

Detailed Description

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described autosomal dominant primary immunodeficiency (PID), caused by the mutations in PIK3CD gene. The manifestations of APDS mainly include recurrent respiratory tract infections, persistent Epstein-Barr virus (EBV)/ cytomegalovirus (CMV)infections, lymphadenopathy, splenomegaly, CD4+T cells lymphopenia, and hyper-IgM syndrome. PIK3CD encodes p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which mainly expresses in leukocytes, being critical for their proliferation, activation and survival. Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mammilian target of rapamycin (mTOR) hyperphosphorylated. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein. Hyperactivation of mTOR increases phosphorylation of kinases and increased glycolysis that results in enhanced proliferation and senescence of terminally differentiated CD8+ Tcell populations.

The optimal treatment for these APDS patients is not yet determined; however, there are many kinds of therapeutic approaches (anti-infection prophylaxis, immunoglobulin replacement, conventional immunosuppressants, PI3K/mTOR inhibitors and hematopoietic stem cell transplantation). The APDS patients frequently receive treatment with immunoglobulin replacement and antibiotics. Hematopoietic stem cell transplantation (HSCT) has been currently curative in APDS patients; however, longer-term follow-up to determine the degree of donor chimerism and efficacy is required. There are several subjects without a prompt suitable matched donor or for whom the critical disease conditions force to postpone HSCT.The mammalian/mechanistic target of inhibitor rapamycin was reported to improve circulating T-cell profiles. Individual patients in previous studies experienced a decrease in nonneoplastic lymphoproliferation while taking rapamycin.

The investigators in this study hope to evaluate the efficacy and safety of rapamycin in the treatment for carefully selected patients with APDS.

Conditions

Activated PI3K-delta Syndrome; Immunodeficiency Primary

Study Design

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

Study Groups

Rapamycin

Treatment for patients with activated phosphoinositide 3-kinase δ syndrome

Group Type: EXPERIMENTAL

Rapamycin

Intervention Type: DRUG

Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mTOR hyperphosphorylated. The mammalian/mechanistic target of rapamycin inhibitor rapamycin may be effective to control the progress of this disease.

Interventions

Rapamycin

Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mTOR hyperphosphorylated. The mammalian/mechanistic target of rapamycin inhibitor rapamycin may be effective to control the progress of this disease.

Intervention Type: DRUG

Other Intervention Names

Sirolimus

Eligibility Criteria

Inclusion Criteria

1. Patients with activated phosphoinositide 3-kinase δ syndrome

2. No more than 18 years old

Exclusion Criteria

1. Patients with serious fungous infection

2. Patients with serious complications

3. Lack of parental consent

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Fudan University

OTHER

Sponsor Role: lead

Responsible Party

Jinqiao Sun

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jinqiao Sun, Ph.D.,M.D

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Fudan University

Locations

Children's Hospital of Fudan University

Shanghai, Shanghai Municipality, China

Children's Hospital of Fudan University

Shanghai, Shanghai Municipality, China

Countries

China

References

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Other Identifiers

RTAPDS

Identifier Type: -

Identifier Source: org_study_id