Sirolimus Effect on Hypertrophic Syndromes Related Gene PIK3CA

Study Overview
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Brief Summary
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It was found that people who have an excessive growth in one or more parts of their body and normal growth in other parts, may have a change in genes responsible for controlling cell growth. This genetic discovery identified a possible treatment for this overgrowth, called Sirolimus. This is a pilot study, which help the investigators prepare a larger international study, which will aim to determine whether a treatment based Sirolimus is able to stop the excessive growth of one or more parties of their body in people who carry a genetic change in the PIK3CA gene (phosphatidylinosilol-3-kinase encoded by the gene PIK3CA).

Detailed Description
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The duration of participation is 15 months: Visit screening: blood test, pre-clinical evaluation, urine collection and chest X-ray. First 6 months: participants will have their overgrowth monitored. This step includes 2 visits taking place at the University Hospital of Dijon: complete clinical evaluation, MRI of the body part by the overgrowth and Dual-energy X-ray absorptiometry (DXA). Next 6 months: participants will take Sirolimus. This step includes 2 visits (4 and 13 weeks after the start of treatment at local hospital): blood test, urine collection and clinical evaluation. and 1 end of study visit after 6 months of treatment taking place at the University Hospital of Dijon: blood test, complete clinical evaluation, urine collection, MRI and DXA. Participants will have several blood and urine tests between visits (1 and 2 weeks after the start of treatment at a local laboratory).

Official Title
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Non-randomised Open Label Pilot Study of Sirolimus Therapy for Segmental Overgrowth Due to PIK3CA- Related Overgrowth

Conditions
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Segmental Overgrowth Disorders Due to PIK3CA

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-zygotic PIK3CA mutation Age: 3-65 years Measurable overgrowth, in current progression or with clinical history of overgrowth progression Patient clinically stable Presence of a disability, social or cosmetic impairment requiring treatment from the patient perspective, Written informed consent form signed and dated by the subject or by the patient's legal representative Exclusion Criteria: Pregnancy or lactation Women and men of reproductive age without any effective method of contraception (during treatment and up to 12 weeks after sirolimus discontinuation) Hypersensitivity to the active substance (sirolimus) or to any of the excipients Impossibility to obtain written informed consent form signed by the subject or the patient's legal representative, or vulnerable adults Treatment with Sirolimus in the last 4 weeks before the trial Personal history of malignancy or current investigations for suspected malignancy Active skin infection requiring antibiotics or antiviral treatments HIV or hepatitis B or C infection Past history of Mycobacterium tuberculosis infection Active pneumopathy Uncontrolled infection Chronic liver disease (ASAT or Alanine amino transférase (ALAT)> 3 times upper normal limit) Stage 3 (or more) chronic renal insufficiency (eGFR< 60mls/min) Neutropenia with neutrophiles < 1.0 x10^9/L Uncontrolled dyslipidemia Inability to attend study visits

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Sirolimus|Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of the relative percentage of the excess tissue volume evolution at the affected site by volumetric MRI. |  | Change from baseline at 6 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure sites of overgrowth by DXA, MRI and circumferential measurements |  | Change from baseline at 6 and 12 months | 
| To determine optimal sirolimus dosing algorithms by plasma assay |  | 12 months | 
| Number of hospitalisation and surgery |  | 12 months | 
| quality of life measured by a questionnaire in the pre- and post-treatment periods | The WHO-QOL-BREF questionnaire will be used for adults. For children, PedsQL™ questionnaire for children and parents report for children questionnaires will be used | At 6 and 12 months |