Intervention: Sirolimus
Trial phase: Phase 2
ATC code: L01EG04 | L04AA10 | S01XA23
SMILES: COC1CC2CCC(C)C(O)(O2)C(=O)C(=O)N2CCCCC2C(=O)OC(C(C)CC2CCC(O)C(OC)C2)CC(=O)C(C)C=C(C)C(O)C(OC)C(=O)C(C)CC(C)C=CC=CC=C1C
Sex: All
Age groups: Child | Adult | Older Adult
Healthy volunteers: No
Participants at risk: 39
Group description: Participants were assessed for sirolimus efficacy at week 0 (before the run-in phase), week 26 (after the run-in phase and before treatment), and at week 52 (after 26 weeks of treatment).

Pharmacokinetic data for sirolimus for children and adults with renal transplants informed dosing algorithms. A target sirolimus plasma concentration of 2-6ng/ml was selected based on in vitro preclinical studies off-label clinical experience, and with the aim of minimizing AEs.
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.