Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas.

Abstract

BACKGROUND:

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers.

METHODS:

We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients.

RESULTS:

None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules.

CONCLUSION:

Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

• Authors: Matthias A Karajannis, Geneviève Legault, Mari Hagiwara, Filippo G Giancotti, Alexander Filatov, Anna Derman, Tsivia Hochman, Judith D Goldberg, Emilio Vega, Jeffrey H Wisoff, John G Golfinos, Amanda Merkelson, J Thomas Roland, Jeffrey C Allen
• Journal: Neuro-oncology (Neuro Oncol) Vol. 16 Issue 2 Pg. 292-7 (Jan 2014) ISSN: 1523-5866 [Electronic] England
• PMID: 24311643 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Everolimus
• Sirolimus

Topics

• Adolescent
• Adult
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Child
• Disease Progression
• Everolimus
• Female
• Follow-Up Studies
• Humans
• Magnetic Resonance Imaging
• Male
• Neoplasm Staging
• Neurofibromatosis 2 (complications, drug therapy, mortality)
• Neuroma, Acoustic (complications, drug therapy, mortality)
• Prognosis
• Prospective Studies
• Sirolimus (analogs & derivatives, pharmacokinetics, therapeutic use)
• Survival Rate
• Young Adult