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

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
National Human Genome Research Institute (NHGRI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for PIK3CA-Related Overgrowth Spectrum (PROS) focused on measuring Clinical Trial, Congenital Malformations, Overgrowth, Pilot Drug Treatment Trial

Eligibility Criteria

3 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patients with PIK3CA gene mutation treated with Sirolimus

Arm Description

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.

Outcomes

Primary Outcome Measures

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)].
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)].

Secondary Outcome Measures

Mean Sirolimus Doses to Achieve the Target Plasma Concentration
To establish optimal sirolimus dosing algorithms for a future RCT.
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).
Number of Hospitalizations and Surgical Interventions
Tracked number of hospitalizations and surgical interventions occurring over the course of the run-in and treatment period.

Full Information

First Posted
April 23, 2015
Last Updated
January 27, 2020
Sponsor
National Human Genome Research Institute (NHGRI)
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1. Study Identification

Unique Protocol Identification Number
NCT02428296
Brief Title
Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation
Official Title
Nonrandomized Open Label Pilot Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation
Study Type
Interventional

2. Study Status

Record Verification Date
February 14, 2018
Overall Recruitment Status
Completed
Study Start Date
April 23, 2015 (undefined)
Primary Completion Date
February 14, 2018 (Actual)
Study Completion Date
February 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Human Genome Research Institute (NHGRI)

4. Oversight

5. Study Description

Brief 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
PIK3CA-Related Overgrowth Spectrum (PROS), Growth Disorder, Genetics
Keywords
Clinical Trial, Congenital Malformations, Overgrowth, Pilot Drug Treatment Trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patients with PIK3CA gene mutation treated with Sirolimus
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Intervention Description
Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.
Primary Outcome Measure Information:
Title
Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA
Description
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)].
Time Frame
Run-in (0-26 weeks), treatment (26-52 weeks)
Title
Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by MRI Scan
Description
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)].
Time Frame
Run-in (0-26 weeks), treatment (26-52 weeks)
Secondary Outcome Measure Information:
Title
Mean Sirolimus Doses to Achieve the Target Plasma Concentration
Description
To establish optimal sirolimus dosing algorithms for a future RCT.
Time Frame
Between 6 months and 12 months
Title
Additional Measure of Efficacy: Quality of Life Assessment
Description
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).
Time Frame
baseline (0 months) and end of treatment (12 months)
Title
Number of Hospitalizations and Surgical Interventions
Description
Tracked number of hospitalizations and surgical interventions occurring over the course of the run-in and treatment period.
Time Frame
Run-in (0-26 weeks) and treatment (27-52 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kim M Keppler-Noreuil, M.D.
Organizational Affiliation
National Human Genome Research Institute (NHGRI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22729222
Citation
Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet. 2012 Jun 24;44(8):928-33. doi: 10.1038/ng.2332.
Results Reference
background
PubMed Identifier
25557259
Citation
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015 Feb;167A(2):287-95. doi: 10.1002/ajmg.a.36836. Epub 2014 Dec 31.
Results Reference
background
PubMed Identifier
24782230
Citation
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VE, Blumhorst C, Darling T, Tosi LL, Huson SM, Whitehouse RW, Jakkula E, Grant I, Balasubramanian M, Chandler KE, Fraser JL, Gucev Z, Crow YJ, Brennan LM, Clark R, Sellars EA, Pena LD, Krishnamurty V, Shuen A, Braverman N, Cunningham ML, Sutton VR, Tasic V, Graham JM Jr, Geer J Jr, Henderson A, Semple RK, Biesecker LG. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014 Jul;164A(7):1713-33. doi: 10.1002/ajmg.a.36552. Epub 2014 Apr 29.
Results Reference
background
PubMed Identifier
30270358
Citation
Parker VER, Keppler-Noreuil KM, Faivre L, Luu M, Oden NL, De Silva L, Sapp JC, Andrews K, Bardou M, Chen KY, Darling TN, Gautier E, Goldspiel BR, Hadj-Rabia S, Harris J, Kounidas G, Kumar P, Lindhurst MJ, Loffroy R, Martin L, Phan A, Rother KI, Widemann BC, Wolters PL, Coubes C, Pinson L, Willems M, Vincent-Delorme C; PROMISE Working Group; Vabres P, Semple RK, Biesecker LG. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med. 2019 May;21(5):1189-1198. doi: 10.1038/s41436-018-0297-9. Epub 2018 Oct 1.
Results Reference
result
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2015-HG-0120.html
Description
NIH Clinical Center Detailed Web Page

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

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