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

January 27, 2020 updated by: National Human Genome Research Institute (NHGRI)

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Actual)

39

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 63 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional 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
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
Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA
Time Frame: Run-in (0-26 weeks), treatment (26-52 weeks)

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
Time Frame: Run-in (0-26 weeks), treatment (26-52 weeks)

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
Time Frame: Between 6 months and 12 months
To establish optimal sirolimus dosing algorithms for a future RCT.
Between 6 months and 12 months
Additional Measure of Efficacy: Quality of Life Assessment
Time Frame: baseline (0 months) and end of treatment (12 months)

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
Time Frame: Run-in (0-26 weeks) and treatment (27-52 weeks)
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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Human Genome Research Institute (NHGRI)

Investigators

  • Principal Investigator: Kim M Keppler-Noreuil, M.D., National Human Genome Research Institute (NHGRI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 23, 2015

Primary Completion (Actual)

February 14, 2018

Study Completion (Actual)

February 14, 2018

Study Registration Dates

First Submitted

April 23, 2015

First Submitted That Met QC Criteria

April 23, 2015

First Posted (Estimate)

April 28, 2015

Study Record Updates

Last Update Posted (Actual)

February 5, 2020

Last Update Submitted That Met QC Criteria

January 27, 2020

Last Verified

February 14, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 150120
  • 15-HG-0120 (Other Identifier: National Institutes of Health)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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