Trial document

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Trial Description

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Open Label Phase II Study of Everolimus (RAD001) in Patients With Segmental Overgrowth Syndrome

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Trial Acronym


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URL of the Trial


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Brief Summary in Lay Language

This is an open-label, multicenter, single-arm, phase II clinical trial of Everolimus
(RAD001) in patients with segmental overgrowth syndrome.

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Brief Summary in Scientific Language

Segmental overgrowth syndromes are very rare diseases with an extremely relevant genetic
background. In some of them, only about 200 cases are known worldwide, such as for example
the Proteus syndrome which presents with asymmetric and fast growth of extremities. Further
overgrowth diseases are the SOLAMEN and the CLOVE syndrome with lipomatosis, vascular
malformations and epidermal nevus as well as the Cowden syndrome with multiple hamartomas
and the Bannayan-Riley-Ruvalcaba syndrome with lipomatosis and macrocephalus. The patients
with overgrowth syndromes all show close clinical overlap. For several years, clinical
criteria (phenotype) for diagnosis and discrimination of these syndromes have been defined.

Results of genetic research can today help to diagnose most of the segmental overgrowth
syndromes which means they can clearly be named. Genes of the PI3K/AKT/PTEN/mTOR signalling
pathway have been identified to be causative for some of these syndromes. PTEN germline
mutations have been known to be present in SOLAMEN, Cowden and Ruvalcaba syndrome patients
all showing tissue overgrowth and close clinical overlap. However, very rarely, somatic PTEN
mutations could be detected in surgical specimen of lipomas or hamartomas of other segmental
overgrowth patients. Only recently, recurrent somatic activating mutations of AKT1 have been
identified in overgrowth tissue of Proteus syndrome patients. Because AKT1 is also activated
by loss-of-function mutations in PTEN, patients with syndromes harbouring germline PTEN
mutations (SOLAMEN, Cowden and Ruvalcaba) and Proteus syndrome patients with activating
mutations of AKT1 show close overlap in clinical manifestations. Furthermore, somatic PI3KCA
mutations have been described to be responsible for the CLOVE syndrome, again a
phenotypically closely related variant of the other overgrowth syndromes. These genetic
results confirmed that patients with overgrowth all share a common feature involving the
PI3K/AKT/PTEN/mTOR signal pathway.

Next to surgical approaches in functional handicapped patients, a standard medical therapy
is not available. Therefore, in most cases, a watch-and-wait strategy is followed. Taking
into account the genetic background of segmental overgrowth patients, mTOR is a promising
target for a possible medical treatment. For example, because the direct molecular
consequence of PTEN loss-of-function is an aberrant activation of the mTOR pathway,
targeting mTOR holds the promise of a causative treatment in PTEN-positive segmental
overgrowth patients.

Until today, three case reports have described the successful use of the mTOR inhibitor
Rapamycin for the therapy of patients with segmental overgrowth and PTEN germline mutation.
The Investigator recently started with "off label" use of Rapamycin in these patients. First
results with successfully treated patients have been presented at The Annual meeting of the
German Society of Human Genetics in 2011 and the meeting of the International Society on the
Studies of Vascular Anomalies in 2012. In one patient with segmental overgrowth syndrome and
response to Rapamycin, the investigators could identify a PI3KCA mutation in one lesion.
This case is currently prepared for publication. Interestingly, response on mTOR inhibition
could be demonstrated in some patients although lack of mutation in the published genes
responsible for overgrowth syndromes.

A clinical trial sponsored by the National Cancer Institute tested the ability of Rapamycin
to decrease the activity of proteins that are regulated by mTOR in both benign and cancerous
tumour tissue in Cowden syndrome patients (NCT00971789). Only patients over the age of 18
years were included and multiple biopsies were performed before starting treatment and
during therapy with Rapamycin.

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Organizational Data

  •   DRKS00009508
  •   2015/10/09
  •   2015/03/18
  •   yes
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Secondary IDs

  •   2014-004019-35 
  •   NCT02569125  (
  •   CRAD001CDE40T  (Jochen Roessler)
  •   2014-004019-35 
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Health Condition or Problem studied

  •   Segmental Overgrowth Syndrome
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Interventions/Observational Groups

  •   Drug: Everolimus
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  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   II
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Primary Outcome

- Number of patients with partial or complete response measured by MRI.; time frame: until 12 months

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Secondary Outcome


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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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  •   2016/01/31
  •   18
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   1   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Male or female patients aged ≥ 1 years.

2. Signed written informed consent (patient older than 18 years or person(s) having the
care and custody of the patient younger than 18 years).

3. Segmental overgrowth syndrome patients independently of genetic background (that
means with/ without PTEN germline mutations or with/without AKT/PI3K somatic
mutations in an overgrowth lesion).

4. Patients who meet clinical criteria for segmental overgrowth syndromes, including a
soft tissue lesion composed of one or several tissue components such as fat, vessels,
muscle, muscle or connective tissue.

5. Identification of a target lesion by MRI > 5 cm3. The target lesion must be
externally visible (photos) and composed by soft 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 (and female partners of male
patients) must use adequate contraceptive measures while on study and for up to 8
weeks after ending treatment.

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Exclusion Criteria

1. Any concurrent therapy with chemotherapy agents or biologic agents or radiation

2. Patients who have received live vaccines in the past 30 days prior to informed

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 interstitial lung disease, pneumonitis or with bleeding

6. Patients with prior use of Everolimus or other mTOR inhibitors such as f.e. Rapamycin
or any analogue within the last 6 months; regardless of therapeutic effect, but with
risk assessment due to former side effects.

7. Any planned surgery within study period.

8. Pre-existing chronic wounds.

9. Triglycerides > 400 mg/dL (> 4.5 mmol/L) or total cholesterol > 300 mg/dL (> 7.8

10. Creatinine clearance ≤ 60 mL/min (Cockcroft and Gault formula).

11. Proteinuria ≥ 30 mg/dL on dipstick and 24 hours proteinuria > 0.8 g/24 hours.

12. Intake of St John's Wort and/or grapefruit and grapefruit juice.

13. Any severe and/or uncontrolled medical conditions which could cause unacceptable
safety risks:

- 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).

14. Patients with a known hypersensitivity to Everolimus or other mTOR inhibitors such as
f.e. Rapamycin or any analogs or to its excipients.

15. Patients unwilling to or unable to comply with the planned therapeutic intervention
or to comply with the study treatment visits including blood sample collection within
the protocol.

16. Female patients who are pregnant or breast feeding, or patients of reproductive
potential who are not using effective birth control methods. If barrier
contraceptives are used, they must be continued throughout the study by both sexes.

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  • start of 1:1-Block address primary-sponsor
    • Jochen Roessler
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    • Clinical Trials Unit Freiburg
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    • University Hospital Freiburg
    • Jochen Roessler, Professor 
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    • University Hospital Freiburg
    • Jochen Roessler, Professor 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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  •   Recruiting withdrawn before recruiting started
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Trial Publications, Results and other Documents

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The parameters in and DRKS are not identical. Therefore the data import from required adjustments. For full details please see the DRKS FAQs .
  •   5
  •   2016/02/24
* This entry means the parameter is not applicable or has not been set.