Sirolimus Effect on Hypertrophic Syndromes Related Gene PIK3CA (PROMISE)

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).

Study Overview

• Status: Completed
• Conditions: Segmental Overgrowth Disorders Due to PIK3CA
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
    • CHU d'Angers
  • Bordeaux, France, 33076
    • CHU de Bordeaux - GH Pellegrin
  • Dijon, France, 21079
    • CHU de Dijon
  • Lille, France, 59037
    • Hôpital Jeanne de Flandre
  • Montpellier, France, 34295
    • CHRU de Montpellier - Hôpital Saint-Eloi
  • Nancy, France, 54511
    • Hopitaux de Brabois Chu Nancy
  • Nantes, France, 44093
    • Hôpital mère-enfant de Nantes
  • Paris, France, 75015
    • CHU Paris - Necker
  • Pierre-Bénite, France, 69495
    • HCL Lyon - CH Lyon Sud
  • Toulouse, France, 31059
    • Pôle Cardiovasculaire et Métabolique - Hôpital Larrey
  • Tours, France, 37044
    • CHRU de Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Dijon

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: May 4, 2015
• First Submitted That Met QC Criteria: May 11, 2015
• First Posted (Estimate): May 14, 2015

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: October 1, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 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: OLIVIER-FAIVRE Sirolimus