An open label phase II study of Sirolimus in patients with segmental overgrowth syndrome

Phase 2

• Conditions: SEGMENTAL OVERGROWTH SYNDROME; Q85.8; Q87.8; Q87.3; Other phakomatoses, not elsewhere classified; Other specified congenital malformation syndromes, not elsewhere classified; Congenital malformation syndromes involving early overgrowth

• Registration Number: DRKS00010085
• Lead Sponsor: niversitätsklinikum Freiburg

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-11-10
• Study Completion: 2023-07-19
• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: Complete
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1.Male or female patients aged = 3 years (no upper limit)
2.Signed written informed consent (patient = 18 years or person(s) having the care and custody of the patient < 18 years).
3.Ability to understand the nature of the trial and the trial related procedures and to comply with them.
4.Segmental overgrowth syndrome patients independently of genetic background.
These diagnoses include patients with
•CLOVES syndrome, Klippel-Trenaunay-Syndrome and other PIK3CA related overgrowth spectrum diseases
•Proteus syndrome
•PTEN hamartoma tumor syndromes including patients with PTEN hamartoma of soft tissue (PHOST)
•Vascular malformations with significant overgrowth (lesion size of at least 3 cm diameter, externally visible), including but not limited to lymphatic malformations, venous malformations, and fibro-adipose vascular anomaly (FAVA)
5.Identification of at least one measurable target lesion (up to 5 target lesions) with longest diameter more than = 30 mm by MRI. The target lesion(s) must be externally visible (photos) and composed of soft tissue (with one or several tissue components such as fat, vessels, muscle or connective tissue).
6.Normal organ and bone marrow function (i.e. transaminase levels < 2.5 x ULN or serum bilirubin < 1.5 x ULN, hemoglobin > 9 g/dL).
7.Negative urine pregnancy test in females with a childbearing potential (details see section 4.2).
8.If female and of child-bearing potential, documentation of negative pregnancy test prior to enrollment. Sexually active female patients, male patients and female partners of male patients must use adequate contraceptive measures while on study and for up to 12 weeks after ending treatment. (details see section 4.2).

Exclusion Criteria

1.Any concurrent therapy with chemotherapy agents or biologic agents or other immunosuppressive therapy or radiation therapy.
2.Patients who have received live vaccines in the past 30 days prior to informed consent.
3.Patients on medication with CYP3A4 inhibitors/inducers which are not replaced by other equivalent medications for the study period.
4.Patients who have known immunodeficiency or HIV seropositivity.
5.Patients with known history of prior and/or ongoing malignancy within the last 5 years.
6.Patients with known interstitial lung disease, pneumonitis or with bleeding diathesis.
7.Patients with prior use of sirolimus or other mTOR inhibitors or any analogue within the last 6 months
8.Any planned surgery within study period related to overgrowth lesions.
9.Pre-existing chronic wounds.
10.Triglycerides > 400 mg/dL (> 4.5 mmol/L) or total cholesterol > 300 mg/dl (> 7.8 mmol/L).
11.Creatinine clearance = 60 ml/min (Cockcroft-Gault formula).
12.Proteinuria = 30 mg/dl on dipstick and 24 hours proteinuria > 0.8 g/24 hours.
13.Intake of St John’s Wort and/or grapefruit and grapefruit juice.
14.Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks such as:
•Uncontrolled hypercholesterolemia/ hypertriglyceridemia
•Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).
15.Patients with a known hypersensitivity to sirolimus or other mTOR inhibitors or any analogs or to its excipients.
16.Patients unwilling to or unable to comply with the planned therapeutic regimen or to comply with the study treatment visits including blood sample collection within the protocol.
17.Female patients who are pregnant or breast feeding, or patients of reproductive potential who are not using effective birth control methods (see: inclusion criteria). If barrier contraceptives are used, they must be continued throughout the study by both sexes.
18.Patients must abstain from donating blood, semen, or sperm during participation in the study until 3 months after the end of participation in the study

Study & Design

• Study Type: interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Best response: Complete Remission (CR) or Partial Remission (PR) until 6 months after baseline (start of study therapy) measured by MRI according to response criteria