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
Intervention: Sirolimus
Intervention description: Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.
Intervention MeSH terms: Sirolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 3 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Clinical Trial; Congenital Malformations; Overgrowth; Pilot Drug Treatment Trial

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Age: greater than or equal to 3 years to less than or equal to 65 years

          -  Male or Female

          -  Confirmed PIK3CA somatic mutation

          -  Measurably progressive overgrowth, in current progression or with clinical history of
             overgrowth progression

          -  Adequate Bone Marrow Function Defined as:

               -  Peripheral absolute neutrophil count (ANC) greater than or equal to
                  1500/microliter, except for those participants with an absolute neutrophil count
                  (ANC) of 1000-1500, caused by a benign condition associated with moderately
                  decreased neutrophils known as Benign Ethnic Neutropenia (BEN), d those who have
                  an ANC of 1000-1500 caused by a confirmed infection, which resolves with
                  treatment of infection to greater than or equal to 1500.

               -  Platelet count less than or equal to 100,000/microliter

               -  Hemoglobin less than or equal to 10.0 gm/dL

          -  Adequate Renal Function Defined as:

          -  A serum creatinine based on age as follows:

               -  Age (years) [Maximum Serum Creatinine (mg/dl)]

               -  Less than or equal to 5 [0.8 mg/dl]

               -  5 less than age less than or equal to10 [1.0 mg/dl]

               -  10 less than age less than or equal to 15 [1.2 mg/dl]

               -  Less than 15 [1.5 mg/dl]

          -  OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73
             m2

               -  Adequate Liver Function Defined As:

                    -  Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 x
                       upper limit of normal (ULN) for age, and

                    -  SGPT (ALT) less than or equal to 5 x upper limit of normal (ULN) for age,
                       and

                    -  Serum albumin greater than or equal to 2 g/dL.

               -  Fasting LDL Cholesterol:

                    -  Patients must have a fasting LDL cholesterol of less than or equal to 160
                       mg/d

                    -  All women of childbearing potential and all sexually active male patients
                       must agree to use effective contraception

                    -  Adolescent (15-17 year old) participants who are fluent in English and can
                       thereby complete the pediatric self-report questionnaires and communicate
                       well with the study team but whose parent(s) and/or legal guardian are
                       primarily Spanish-speaking.

        EXCLUSION CRITERIA:

        The participant may not enter the study if ANY of the following apply:

          -  Age less than 3 years or greater than 65 years

          -  Pregnant or breastfeeding

          -  Women and men of reproductive age without an effective method of contraception (during
             treatment and up to 12 weeks after sirolimus discontinuation)

          -  Hypersensitivity to sirolimus or any of the excipients

          -  Any current medical disorder or medication likely to impair ability to follow the
             study protocol safely and effectively

          -  Incapacity to give informed consent

          -  Sirolimus treatment in the prior 4 weeks

          -  If less than 3 months post-surgery

          -  Prior malignancy or ongoing investigations for malignancy

          -  Active skin infections requiring antibiotics or anti-viral medication

          -  HCV/HBV/HIV seropositivity

          -  Previous/ active MTB infection

          -  Pneumonitis

          -  Research radiation exposure within previous 12 months

          -  Adult participants or participants under the age of 15 years with insufficient English
             language proficiency to complete informed consent and quality of life measures

        We propose to restrict participation in this study to those with sufficient English
        language skills to complete the quality of life measures we will employ among all three
        study sites, as many of the specific quality of life measures we are employing at the NIH
        only are not available in other languages.