E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Segmental overgrowth syndrome |
Überwuchssyndrom |
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E.1.1.1 | Medical condition in easily understood language |
Segmental overgrowth syndrome |
Überwuchssyndrom |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the effect of sirolimus to reduce the size of defined target lesions in patients with segmental overgrowth syndromes. |
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E.2.2 | Secondary objectives of the trial |
To evaluate changes in disfigurement assessed by serial digital photograph To evaluate changes in health-related Quality of Life To evaluate changes in pain To evaluate changes in neuropsychological testing compared to baseline values. To evaluate changes in biomarkers compared to respective baseline values. To assess the inhibition of the mTOR pathway. Assessment of safety. Study drug compliance.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. 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.
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Best response: Complete Remission (CR), or Partial Remission (PR) until 6 months after start of therapy period (baseline) measured by MRI according to response criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
until 6 months after baseline |
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E.5.2 | Secondary end point(s) |
Morphological changes in disfigurement compared to baseline by using a scale for external validation documented by photography after 3, 6 and 9 months of therapy Changes in Quality of life after 3, 6 and 9 months of therapy compared to baseline (for patients ≥ 4 and ≤ 17 years of age by KINDL® parents and Kiddy-KINDL® Kids 4-6 years, Kid-KINDL® Kids 7-13 years, Kiddo-KINDL® Teenager 14-17 years, and for patients ≥ 18 by WHOQOL-BREF as well as Lansky (<16 years)/Karnofsky scale) Changes in pain after 3, 6 and 9 months of therapy compared to baseline by visual pain scales for adults and children Changes in neuropsychological tests (using Strengths and Difficulties Questionnaire (SDQ) Kids (6-11 years), Parents and Erwachsene ≥ 18 years after 3, 6 and 6 9 months of therapy compared to baseline. Changes in IGFBP-3, IGF-1, VEGF compared to baseline values after 3, 6 and 6 9 months of therapyafter start of study treatment (baseline). Inhibition of mTOR in PBMCs assessed by immunoblotting after 3, 6 and 9 months after start of study treatment (baseline). Safety will be determined by observation of any adverse or serious adverse events. Evaluations will include clinical and laboratory assessments performed at the time points described in the flow chart. Criteria for assessment of safety will be based on standard criteria for monitoring, assessing, and reporting of adverse events (CTCAE criteria v. 5.0). Study drug compliance measured with patient diary.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
CR or PR after 6 months Changes in Quality of life after 3, 6 and 9 months. Changes in pain after 3, 6 and 9 months. Changes in neuropsychological tests after 3, 6 and 9 months. Morphological changes after 3, 6 and 9 months. Changes in IGFBP-3, IGF, VEGF after 3, 6 and 9 months. Inhibition of mTOR in PBMCs after after 3, 6 and 9 months.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 36 |