Sirolimus Effect on Hypertrophic Syndromes Related Gene PIK3CA

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

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).

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).

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