Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation

Study Overview
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Brief Summary
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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
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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).

Official Title
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Nonrandomized Open Label Pilot Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation

Conditions
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PIK3CA-Related Overgrowth Spectrum (PROS), Growth Disorder, Genetics

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with PIK3CA gene mutation treated with Sirolimus<br>This is a single-arm, non-randomized, open-label study for the treatment of segmental overgrowth disorders (somatic PIK3CA gene mutation) with Sirolimus in thirty-nine patients. | Drug: Sirolimus<br>* Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA | The primary outcome measures will use quantitative DXA scan of the affected and unaffected body part (s) to demonstrate negative change in fibrofatty, muscular, and/or bony overgrowth. Absolute volumes of affected and unaffected tissue at week 0 (designated X), week 26 (designated Y), and week 52 (designated Z), were compared by taking the difference between the mean value obtained during the run-in period and the mean value obtained during the treatment period. Tissue volume changes (week 0-26 and week 26-52) were designated DELTA, and the percent change % Change. Percent change for the untreated period was [100(Y-X/X)], and for the treated period [100(Z-Y/Y)]. | Run-in (0-26 weeks), treatment (26-52 weeks) | 
| Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by MRI Scan | The outcome was measured as a percent change in tissue volume between the treatment period and run-in period. For volume calculation, IDEAL fat (Dixon sequence) images were visualized using volumetric software (SliceOmatic, TomoVision, Magog, Canada). Morphology segmentation was performed through computation of watershed gradients. Tissues (fat, muscle, bone, and blood vessel) were manually defined and software was used to generate a surrogate of tissue volume using five slices, with manual adjustments where required. Absolute volumes of affected and unaffected tissue at week 0 (designated X), week 26 (designated Y), and week 52 (designated Z), were compared. Tissue volume changes (week 0-26 and week 26-52) were designated DELTA, and the percent change % Change. Percent change for the untreated period was [100(Y-X/X)], and for the treated period [100(Z-Y/Y)]. | Run-in (0-26 weeks), treatment (26-52 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Sirolimus Doses to Achieve the Target Plasma Concentration | To establish optimal sirolimus dosing algorithms for a future RCT. | Between 6 months and 12 months | 
| Additional Measure of Efficacy: Quality of Life Assessment | The World Health Organization Quality of Life-BREF (WHOQOL-BREF) assessment measures four domains related to quality of life (physical health, psychological, social relationships, and environment) and produces both individual domain scores (0-100) a total score on a 0-100 scale (high scores indicate a better quality of life). This measure was used to assess quality of life of parents on behalf of their children, and adult subjects. The Pediatric Quality of Life (PedsQL) assessment is scored on a 0-100 scale (high scores indicate a better health related quality of life). This measure was used to assess quality of life of children. The outcomes are reported as a change in quality of life based on the change in scores from these assessments between baseline (time 0 months) and end of treatment (time 12 months). | baseline (0 months) and end of treatment (12 months) | 
| Number of Hospitalizations and Surgical Interventions | Tracked number of hospitalizations and surgical interventions occurring over the course of the run-in and treatment period. | Run-in (0-26 weeks) and treatment (27-52 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical Trial, Congenital Malformations, Overgrowth, Pilot Drug Treatment Trial