to study search History

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

Organizational Data

DRKS-ID:
DRKS00010085
Recruitment Status:
Recruiting complete, study complete
Date of registration in DRKS:
2016-11-10
Last update in DRKS:
2023-07-20
Registration type:
Prospective

Acronym/abbreviation of the study

SIPA-SOS

URL of the study

http://n/a

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.

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.

Health condition or problem studied

Free text:
SEGMENTAL OVERGROWTH SYNDROME
ICD10:
Q85.8 - Other phakomatoses, not elsewhere classified
ICD10:
Q87.8 - Other specified congenital malformation syndromes, not elsewhere classified
ICD10:
Q87.3 - Congenital malformation syndromes involving early overgrowth
Healthy volunteers:
No

Interventions, Observational Groups

Arm 1:
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

Endpoints

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
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.

Study Design

Purpose:
Treatment
Allocation:
N/A (single arm study)
Control:
  • Uncontrolled/single arm
Phase:
II
Study type:
Interventional
Mechanism of allocation concealment:
No Entry
Blinding:
No
Assignment:
Single (group)
Sequence generation:
No Entry
Who is blinded:
No Entry

Recruitment

Recruitment Status:
Recruiting complete, study complete
Reason if recruiting stopped or withdrawn:
No Entry

Recruitment Locations

Recruitment countries:
  • Germany
Number of study centers:
Multicenter study
Recruitment location(s):
  • University medical center Zentrum für Kinder- und Jugendheilkunde, Pädiatrische Hämatologie und Onkologie Freiburg im Breisgau
  • Medical center Vivantes Klinikum Berlin Neukölln Berlin
  • University medical center Leipzig
  • University medical center Bonn
  • University medical center Klinikum der Universität München, Kinderchirurgische Klinik i. Haunerschen Kinderspital, Ambulanz für plast. Chirurgie, Lindwurmstr. 4, 80337 München München

Recruitment period and number of participants

Planned study start date:
2021-07-15
Actual study start date:
2021-10-22
Planned study completion date:
2023-07-19
Actual Study Completion Date:
2023-07-19
Target Sample Size:
18
Final Sample Size:
18

Inclusion Criteria

Sex:
All
Minimum Age:
3 Years
Maximum Age:
no maximum age
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).

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

Addresses

Primary Sponsor

Universitätsklinikum Freiburg
Hugstetter Strasse 49
79095 Freiburg
Germany
Telephone:
No Entry
Fax:
No Entry
Contact per E-Mail
URL:
http://www.uniklinik-freiburg.de
Investigator Sponsored/Initiated Trial (IST/IIT):
Yes

Contact for Scientific Queries

Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin
Dr. Friedrich Kapp
Mathildenstraße 1
79106 Freiburg
Germany
Telephone:
0761 270-45210
Fax:
No Entry
Contact per E-Mail
URL:
No Entry

Contact for Public Queries

Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin
Dr. Friedrich Kapp
Mathildenstraße 1
79106 Freiburg
Germany
Telephone:
0761 270-45210
Fax:
No Entry
Contact per E-Mail
URL:
No Entry

Principal Investigator

Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin
Dr. Friedrich Kapp
Mathildenstraße 1
79106 Freiburg
Germany
Telephone:
0761 270-45210
Fax:
No Entry
Contact per E-Mail
URL:
No Entry

Sources of Monetary or Material Support

Commercial (pharmaceutical industry, medical engineering industry, etc.)

Pfizer Deutschland GmbH
Linkstraße 10
10785 Berlin
Germany
Telephone:
No Entry
Fax:
No Entry
Contact per E-Mail
URL:
No Entry

Public funding institutions financed by tax money/Government funding body (German Research Foundation (DFG), Federal Ministry of Education and Research (BMBF), etc.)

Deutsche Forschungsgemeinschaft
Kennedyallee 40
53175 Bonn
Germany
Telephone:
No Entry
Fax:
No Entry
Contact per E-Mail
URL:
http://www.dfg.de

Institutional budget, no external funding (budget of sponsor/PI)

Universitätsklinikum Freiburg
Hugstetter Strasse 49
79095 Freiburg
Germany
Telephone:
No Entry
Fax:
No Entry
Contact per E-Mail
URL:
http://www.uniklinik-freiburg.de

Ethics Committee

Address Ethics Committee

Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
Engelberger Str. 21
79106 Freiburg
Germany
Telephone:
+49-761-27072600
Fax:
+49-761-27072630
Contact per E-Mail
URL:
No Entry

Vote of leading Ethics Committee

Date of ethics committee application:
2016-03-02
Ethics committee number:
97/16
Vote of the Ethics Committee:
Approved
Date of the vote:
2016-10-20

Further identification numbers

Other primary registry ID:
No Entry
EudraCT Number:
2015-005416-15
UTN (Universal Trial Number):
No Entry
EUDAMED Number:
No Entry

IPD - Individual Participant Data

Do you plan to make participant-related data (IPD) available to other researchers in an anonymized form?:
Yes
IPD Sharing Plan:
by publication

Study protocol and other study documents

Study protocols:
SIPA-SOS Protokoll V5.0
Study abstract:
No Entry
Other study documents:
No Entry
Background literature:
No Entry
Related DRKS studies:
No Entry

Publication of study results

Planned publication:
No Entry
Publikationen/Studienergebnisse:
No Entry
Date of first publication of study results:
No Entry
DRKS entry published for the first time with results:
No Entry

Basic reporting

Basic Reporting / Results tables:
No Entry
Brief summary of results:
No Entry