Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation
Condition: PIK3CA-Related Overgrowth Spectrum (PROS); Growth Disorder; Genetics
MeSH terms: Growth Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - PIK3CA-related overgrowth spectrum (PROS) is caused by changes in the PIK3CA gene. This
      gene makes a protein that communicates with other proteins in the body to cause cells to
      grow. Alterations in PIK3CA change the chemical signals in the body and cause overgrowth in
      fatty, vascular and other tissues. Sirolimus is a drug that reduces the signals sent by one
      of the proteins in this chemical signaling pathway. Researchers want to learn whether the
      drug sirolimus can reduce or stabilize some of the overgrowth that patients with PROS
      experience.

      Objectives:

      - To measure how the overgrowth of patients with PROS changes over time and whether taking a
      drug called sirolimus can reduce or stabilize a person s overgrowth.

      Eligibility:

      - People ages 3 to 65 years old with a confirmed mutation or alteration of the PIK3CA gene in
      the person s affected tissues (a somatic mutation).

      Design:

        -  Participants will be screened with medical history and genetic counseling.

        -  First 6 months: Participants will have their overgrowth monitored.

        -  Next 6 months: Participants will take sirolimus once or twice a day.

        -  Participants will have to visit the clinic several times, and stay in the area for 4 to
           5 days each time.

        -  Participants will have a one month-long visit to the clinic.

        -  During clinic visits, participants will have:

        -  Blood and urine tests.

        -  Photographs of their physical features.

        -  Scans, including an MRI and DEXA, and possibly x-rays and CT scans.

        -  For the MRI and CT scans, participants will lie in a machine that takes pictures of
           their body.

        -  The DEXA involves a small amount of radiation.

        -  They may have:

        -  Non-invasive heart function tests.

        -  Lung function tests.

        -  Participants will have several blood and urine tests between visits.

        -  Participants will complete surveys and keep a diary of their treatment and side effects.

        -  Participants may visit other health specialists or undergo other tests based on side
           effects.

        -  One month after stopping the study drug, participants will have 1 clinic visit.
    

Detailed description: 
      The primary study objective is to determine the likely size of sirolimus treatment effect.
      The patient population will include male and female subjects, aged greater than or equal to 3
      years and less than or equal to 65 years of age with segmental overgrowth identified to have
      clinical and molecular findings of somatic PIK3CA gene mutation. The planned study size will
      be ten patients seen at the NIHCC. An additional 20 patients will be contributed by two other
      centers, who will be responsible for the conduct of the proposed research at their site, but
      the study procedures and dosing schedule will be identical to enable pooling of results for
      statistical analyses. The study design will be a nonrandomized, open label, phase II pilot
      study of sirolimus treatment. As patients have highly variable clinical presentations, and
      there are no established evidence-based methodologies for measuring serial changes in growth,
      the aim of this pilot study is to establish the optimal methodology for evaluating changes in
      growth to inform the design of a future randomized controlled trial, in addition to
      determining treatment effect size, and evaluating safety and toxicity of low dose sirolimus.
      Overall desired outcome will be reduced size of affected body part, and measures will
      include: reduction in affected tissue (fibroadipose or bone) size by clinical exam
      measurement and by radiological studies (MRI area measurements and/or DXA study measurements
      of fat).
    

Intervention name(s): Sirolimus
Intervention type(s): Drug
Intervention description(s): Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.
Intervention MeSH terms: Sirolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Clinical Trial; Congenital Malformations; Overgrowth; Pilot Drug Treatment Trial