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

Overview

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

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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Eligibility

Locations (4)

Outcomes