Trial document




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  DRKS00010085

Trial Description

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Title

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

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Trial Acronym

SIPA-SOS

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URL of the Trial

http://n/a

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Brief Summary in Lay Language

In this study is has to be determined whether the tissue which has grown out of proportion, is smaller by taking sirolimus. A pathway in the cells of overgrowth syndromes appears to play an important role: it is by the participating molecules called PI3K / Akt / mTOR signaling pathway. Is this pathway disrupted there is an increased activation of the so-called protein molecule "mTOR". This in turn leads to disruption of the development of blood vessels and thus overgrow syndromes. Sirolimus is a substance which inhibits mTOR. It is already being used as an inhibitor of the immune system in organ transplantation and as a medicine for cancer.

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Brief Summary in Scientific Language

Until today, the only therapeutic approach in segmental overgrowth syndromes is by surgery only. Lesions showing overgrowth leading to handicap or discomfort is excised or reduced if possible. Operations have to be repeated regularly as overgrowth is continuously present during lifetime in the patients. A medical treatment, eventually administered continuously during lifetime that could replace the regular surgical procedures has not been available. Three single case reports showed response of overgrowth lesions in patients with PTEN germline mutations to the mTOR inhibitor Sirolimus. In addition, our case report on a patient with a somatic PI3K mutation in an overgrowth lesion showed as well response to Sirolimus (Rössler et al., manuscript in preparation). To scientifically proof the effectiveness of mTOR inhibition to stop overgrowth in segmental overgrowth lesions, a clinical trial has to be realized.

In “pubmed” no clinical trial is reported using Sirolimus in segmental overgrowth syndrome patients. In the database “clinicaltrial.gov” ongoing clinical trials using Sirolimus in segmental overgrowth patients are available, but also including patients with vascular malformations only, w/o phenotype of overgrowth. Furthermore, the company Pfizer has no information on any planned or ongoing clinical trials on Sirolimus and segmental overgrowth syndrome patients as main phenotype. In the planned clinical trial SIPASOS, we propose to study the therapeutic effect of Sirolimus on target lesions in segmental overgrowth patients 3 years of age and older, independently of presence of mutations in the genes of the PI3K/AKT/PTEN/mTOR signal pathway. In the phase II trial design a dose and target blood level range of Sirolimus for children and adults based on literature and own experience was chosen. An early radiological response assessment will be performed after 6 months, a second response assessment after 12 months. Quality of life and neurophysiological tests as well as photographs will be compared to baseline to show further effectiveness of Sirolimus therapy.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00010085
  •   2016/11/10
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  •   yes
  •   Approved
  •   97/16, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2015-005416-15 
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Health Condition or Problem studied

  •   SEGMENTAL OVERGROWTH SYNDROME
  •   Q85.8 -  Other phakomatoses, not elsewhere classified
  •   Q87.8 -  Other specified congenital malformation syndromes, not elsewhere classified
  •   Q87.3 -  Congenital malformation syndromes involving early overgrowth
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Interventions/Observational Groups

  •   6 months therapy period:
    1,6 mg/m² Sirolimus daily over 6 months:
    patients <16 years will take twice daily oral 0.8 mg/m2,
    patients ≥16 years will be treated on a once daily dosage regimen
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   II
  •   No
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Primary Outcome

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

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Secondary Outcome

- Morphological changes in disfigurement compared to baseline by using a scale for external validation documented by photography after 3, 6 und 9 months of therapy.
- Changes in quality of life after 3, 6 und 9 months of therapymonths compared to baseline (KINDL® parents und Kid-KINDL®; Lansky/Karnofsky scale, WHOQOL-BREF).
- Changes in neuropsychological tests (Strengths and Difficulties Questionnaire (SDQ) after 3, 6 und 9 months of therapy compared to baseline.
- Changes in IGFBP-3, IGF, VEGF compared to baseline values 3, 6 und 9 months after start of study therapy.
- Inhibition of mTOR in peripheral blood mononuclear cells (PBMCs) assessed by immunoblotting 3, 6 und 9 months after start of study therapy (baseline).
- Assessment of safety: 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. 4.0).
- Study drug compliance measured with patient diary.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
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Recruitment

  •   Actual
  •   2021/10/22
  •   18
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   3   Years
  •   no maximum age
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Additional 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).

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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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Addresses

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    • Universitätsklinikum Freiburg
    • Hugstetter Strasse 49
    • 79095  Freiburg
    • Germany
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    • Pfizer Deutschland GmbH
    • Linkstraße 10
    • 10785  Berlin
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    • Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin
    • Mr.  Dr.  Friedrich  Kapp 
    • Mathildenstraße 1
    • 79106  Freiburg
    • Germany
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    • Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin
    • Mr.  Dr.  Friedrich  Kapp 
    • Mathildenstraße 1
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Freiburg
    • Hugstetter Strasse 49
    • 79095  Freiburg
    • Germany
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    • Pfizer Deutschland GmbH
    • Linkstraße 10
    • 10785  Berlin
    • Germany
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    • Deutsche Forschungsgemeinschaft
    • Kennedyallee 40
    • 53175  Bonn
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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