Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome

Efficacy and Safety of Rapamycin Therapy for Patients With Activated Phosphoinositide 3-Kinase δ Syndrome

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).

Study Overview

• Status: Recruiting
• Conditions: Activated PI3K-delta Syndrome; Immunodeficiency Primary
• Intervention / Treatment: Drug: Rapamycin

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Weili Yan, Ph.D.; Phone Number: 86-21-64931913; Email: yanwl@fudan.edu.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 201102
      • Recruiting
      • Children's Hospital of Fudan University
    • Shanghai, Shanghai, China
      • Recruiting
      • Children's Hospital of Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Rapamycin; Treatment for patients with activated phosphoinositide 3-kinase δ syndrome	Drug: 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.; Other Names: Sirolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Recurrent Infections	Frequency of recurrent infections of the patients as indicators of rapamycin efficacy.	5 years
Hepatosplenomegaly	Changes in hepatosplenomegaly with rapamycin treatment.	5 years
Lymphocyte subset	The changes of lymphocytes subset were evaluated by flow cytometry.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events	Unexpected toxic adverse events during and after using rapamycin	5 years

Collaborators and Investigators

• Sponsor: Children's Hospital of Fudan University

Publications and helpful links

General Publications

• Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, Goodlad JR, Farmer G, Steele CL, Leahy TR, Doffinger R, Baxendale H, Bernatoniene J, Edgar JD, Longhurst HJ, Ehl S, Speckmann C, Grimbacher B, Sediva A, Milota T, Faust SN, Williams AP, Hayman G, Kucuk ZY, Hague R, French P, Brooker R, Forsyth P, Herriot R, Cancrini C, Palma P, Ariganello P, Conlon N, Feighery C, Gavin PJ, Jones A, Imai K, Ibrahim MA, Markelj G, Abinun M, Rieux-Laucat F, Latour S, Pellier I, Fischer A, Touzot F, Casanova JL, Durandy A, Burns SO, Savic S, Kumararatne DS, Moshous D, Kracker S, Vanhaesebroeck B, Okkenhaug K, Picard C, Nejentsev S, Condliffe AM, Cant AJ. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017 Feb;139(2):597-606.e4. doi: 10.1016/j.jaci.2016.06.021. Epub 2016 Jul 16.
• Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014 Jan;15(1):88-97. doi: 10.1038/ni.2771. Epub 2013 Oct 28.
• Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, Kato T, Okano T, Takashima T, Kobayashi K, Kimura M, Kunitsu T, Maruo Y, Kanegane H, Takagi M, Yoshida K, Okuno Y, Muramatsu H, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kojima S, Ogawa S, Ohara O, Okada S, Kobayashi M, Morio T, Nonoyama S. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016 Dec;138(6):1672-1680.e10. doi: 10.1016/j.jaci.2016.03.055. Epub 2016 Jul 14.
• Vignesh P, Rawat A, Singh S. An Update on the Use of Immunomodulators in Primary Immunodeficiencies. Clin Rev Allergy Immunol. 2017 Apr;52(2):287-303. doi: 10.1007/s12016-016-8591-2.
• Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debre M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.
• Walsh CM, Fruman DA. Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling. J Clin Invest. 2014 Sep;124(9):3688-90. doi: 10.1172/JCI77198. Epub 2014 Aug 18.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2017
• Primary Completion (Anticipated): November 30, 2022
• Study Completion (Anticipated): November 30, 2022

Study Registration Dates

• First Submitted: December 12, 2017
• First Submitted That Met QC Criteria: December 19, 2017
• First Posted (Actual): December 26, 2017

Study Record Updates

• Last Update Posted (Actual): March 23, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Activated PI3K-delta Syndrome; Immunodeficiency Primary; Akt/mTOR pathway; Rapamycin Therapy; Hyperphosphorylation
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Disease; Genetic Diseases, Inborn; Syndrome; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: RTAPDS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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