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

NCT02428296 | Completed Phase 2 Results

• 2 other identifiers: 15012015-HG-0120
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Clinical Trial; Congenital Malformations; Overgrowth; Pilot Drug Treatment Trial

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Mean Sirolimus Doses to Achieve the Target Plasma Concentration

  Between 6 months and 12 months

• Additional Measure of Efficacy: Quality of Life Assessment

  baseline (0 months) and end of treatment (12 months)

• Number of Hospitalizations and Surgical Interventions

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

Study Arms (1)

Patients with PIK3CA gene mutation treated with Sirolimus

EXPERIMENTAL

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

Interventions

Sirolimus DRUG

Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.

Patients with PIK3CA gene mutation treated with Sirolimus

Eligibility Criteria

• Age: 3 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \[0.8 mg/dl\]
• less than age less than or equal to10 \[1.0 mg/dl\]
• less than age less than or equal to 15 \[1.2 mg/dl\]
• Less than 15 \[1.5 mg/dl\]

You may not qualify if:

• 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

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 22729222 BACKGROUND

• 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.

  PMID: 25557259 BACKGROUND

• 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.

  PMID: 24782230 BACKGROUND

• 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.

  PMID: 30270358 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Growth Disorders; Congenital Abnormalities

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Phenotypic heterogeneity; post hoc subanalyses and QoL assessments had small sample sizes; overestimation of AEs; interruption of treatment due to intercurrent AEs; asymmetric overgrowth not included in primary outcome analysis

Results Point of Contact

• Title: Dr. Kim Keppler-Noreuil
• Organization: Children's National Medical Center

kkepplerno@childrensnational.org

2024766287

Study Officials

• Kim M Keppler-Noreuil, M.D.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2015
• First Posted: April 28, 2015
• Study Start: April 23, 2015
• Primary Completion: February 14, 2018
• Study Completion: February 14, 2018
• Last Updated: February 5, 2020
• Results First Posted: January 27, 2020

Record last verified: 2018-02-14

Locations

US (1)