Dataset Information

AT-30EFFECTS OF EVEROLIMUS ON MENINGIOMA GROWTH IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2

ABSTRACT: BACKGROUND: Vestibular schwannomas (VS) and meningiomas are associated with biallelic loss of NF2, and may arise sporadically or in the context of the tumor predisposition syndrome neurofibromatosis type 2. Loss of NF2 activates the mammalian target of rapamycin (mTOR) pathway, and published in vitro and in vivo data indicate that mTOR inhibition may be effective in the treatment of NF2-deficient VS and meningiomas. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with anti-tumor activity in a variety of tumors. METHODS: We conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated with everolimus on our prospective phase II clinical trial (ClinicalTrials.gov NCT01419639). Everolimus was administered at a daily dose of 10 mg in continuous 28-day courses for up to 12 courses. In this retrospective study, we included patients with at least one volumetrically measurable meningioma (>0.5 cc) who received at least six 28-day courses of therapy. Tumor response was assessed with brain MRI every three months using three-dimensional volumetric analysis. RESULTS: Three patients met criteria and had 10 evaluable meningiomas, with a total combined volume of 11.84 cc at baseline (median 1.20 cc, range 0.53–3.00 cc). Median time on therapy was 9 months (range 6–12 months). Total combined meningioma volume remained stable during treatment (-1.8%). Correspondingly, none of the individual tumors analyzed met criteria for volumetric response or progression during the treatment period (range -10% to +9.4%). CONCLUSIONS: Neither objective response nor progression was appreciated in meningiomas patients during a median treatment duration of 6 months. Further clinical studies will be required to determine whether everolimus affects meningioma growth velocity in patients with NF2. To better understand pharmacologic mTOR signaling pathway modulation in human VS and meningiomas in vivo, we are currently conducting a multi-center pharmacodynamic/pharmacokinetic (“phase 0”) study with everolimus (NCT01880749).

SUBMITTER: Karajannis M

PROVIDER: S-EPMC4217809 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundActivation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.MethodsChildren with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.ResultsTwenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.ConclusionIndividuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.

Dataset Information

AT-30EFFECTS OF EVEROLIMUS ON MENINGIOMA GROWTH IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets