IGF-I influences everolimus activity in medullary thyroid carcinoma

Context: Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells. It has been previously demonstrated that insulin-like growth factor I (IGF-I) protects MTC from the effects of antiproliferative drugs. Everolimus, an mTOR inhibitor, has shown potent antiproliferative effects in a human MTC cell line, TT, and in two human MTC primary cultures. Objective: To verify whether IGF-I may influence the effects of everolimus in a group of human MTC primary cultures. Design: We collected 18 MTCs that were dispersed in primary cultures, treated without or with 10 nM-1 mu M everolimus and/or 50 nM IGF-I. Cell viability was evaluated after 48 h, and calcitonin (CT) secretion was assessed after a 6 h incubation. IGF-I receptor downstream signaling protein expression profile was also investigated. Results: Everolimus significantly reduced cell viability in eight MTC [by similar to 20%; P < 0.01 vs. control; everolimus-responders (E-R) MTCs], while cell viability did not change in 10 MTCs [everolimus-non-responders (E-NR) MTCs]. In E-R MTCs, IGF-I blocked the antiproliferative effects of everolimus that did not affect CT secretion, but blocked the stimulatory effects of IGF-I on this parameter. IGF-I receptor downstream signaling proteins were expressed at higher levels in E-NR MTC as compared to E-R MTCs. Conclusion: IGF-I protects a subset of MTC primary cultures from the antiproliferative effects of everolimus and stimulates CT secretion by an mTOR mediated pathway that, in turn, may represent a therapeutic target in the treatment of aggressive MTCs

First reported double drug–drug interaction in a cancer renal patient under everolimus treatment: therapeutic drug monitoring and review of literature

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities

Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the Spine

Objective: Spinal metastatic disease remains a major problem of oncological diseases. Patients affectedmay suffer pain, spinal instability, and severe neurological deficits. Today, palliative surgery and radiotherapy are the mainstays of therapy. In contrast, preventive treatment strategies or treatment concepts for an early stage are lacking. Here, we have used a syngeneic, experimental spine metastases model in the mouse to test the efficacy of mTOR inhibition and anti-angiogenesis on the formation and progression of spinal melanoma metastases. Methods: We used our previously established syngeneic spinal metastases mouse model by injecting luciferin-transfected B16 melanoma cells into the common carotid artery. Following injection, mice were treated with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) complex, axitinib, a tyrosine kinase inhibitor, that blocks vascular endothelial growth factor receptors (VEGFR) 1-3, as well as placebo. Animals were followed-up daily by neurological assessment and by repeat in vivo bioluminescence imaging. With occurrence of neurological deficits, a spinal MRI was performed, and mice were sacrificed. The whole spine was dissected free and analyzed by immunohistochemical techniques. Results: Overall survival was 23 days in the control group, significantly prolonged to 30 days (p = 0.04) in the everolimus group, and to 28 days (p = 0.04) in the axitinib group. While 78% of mice in the placebo group developed symptomatic metastatic epidural spinal cord compression, only 50% did so in the treatment groups. The mean time to manifestation of paralysis was 22 days in the control group, 26 days (p = 0.10) in the everolimus group, and 27 days (p = 0.06) in the axitinib group. Screening for spinal metastases by bioluminescence imaging on two different time points showed a decrease in metastatic tumor formation in the treatment groups compared to the controls. Immunohistochemical analysis confirmed the bioactivity of the two compounds: The Ki67 proliferation labeling index was reduced in the everolimus group and numbers of CD31 positive endothelial cells were reduced in the axitinib group. Conclusion: Both, the mTOR inhibitor everolimus as well as antiangiogenetic effects by the VEGFR inhibitor axitinib showed potential to prevent and retard formation of symptomatic spinal metastases. However, the therapeutic efficacy was only mild in this experimental model

Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non-mTOR-mediated etiologies.

The present study was designed to examine the potential cellular antiseizure mechanisms of everolimus, a mechanistic target of rapamycin (mTOR) pathway blocker, in pediatric epilepsy cases. Cortical tissue samples obtained from pediatric patients (n&nbsp;=&nbsp;11, ages 0.67-6.75&nbsp;years) undergoing surgical resections for the treatment of their pharmacoresistant epilepsy were examined electrophysiologically in ex&nbsp;vivo slices. The cohort included mTOR-mediated pathologies (tuberous sclerosis complex [TSC] and severe cortical dysplasia [CD]) as well as non-mTOR-mediated pathologies (tumor and perinatal infarct). Bath application of everolimus (2&nbsp;μm) had practically no effect on spontaneous inhibitory postsynaptic activity. In contrast, long-term application of everolimus reduced spontaneous excitatory postsynaptic activity, burst discharges induced by blockade of γ-aminobutyric acid A (GABAA) receptors, and epileptiform activity generated by 4-aminopyridine, a K+ channel blocker. The antiseizure effects were more pronounced in TSC and CD cases, whereas in non-mTOR-mediated pathologies, the effects were subtle at best. These results support further clinical trials of everolimus in mTOR pathway-mediated pathologies and emphasize that the effects require sustained exposure over time

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study

Background: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. Results: In the total population (N = 334),median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211),median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%),anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. Conclusions: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC

Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma

This study aimed at determining the recommended dose of the mammalian target of rapamycin inhibitor everolimus in combination with mitomycin C (MMC) in patients with previously treated metastatic esophagogastric cancer. In this phase I trial, patients received escalated doses of oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m2 every 3 weeks. Endpoints were the dose-limiting toxicity (DLT), safety, and response rates. Tumor tissues were tested for HER2-status and mutations in the PTEN, PIK3CA, AKT1, CTNNB1, and E-cadherin type 1 genes. Sixteen patients (12 male, four female) with gastric/gastroesophageal junction cancer were included. All patients were previously treated with a platinum-based chemotherapy. Treatment cohorts were: 5 mg/day, three patients; 7.5 mg/day, three patients; and 10 mg/day, 10 patients. No DLTs occurred during dose escalation. Most frequent grade 3 toxicities were leukopenia (18.8%) and neutropenia (18.8%). All other grade 3 toxicities were below 10%. No grade 4 toxicities occurred. Three (18.8%) patients experienced partial responses and four patients had stable disease (SD). Antitumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)-criteria was highest in the 10 mg/day cohort. No associations between HER2-status or detected mutations and response were observed. The recommended dose of everolimus combined with MMC is 10 mg/day. Encouraging signs of antitumor activity were seen (http://www.ClinicalTrials.gov; Clinical trial registration number: NCT01042782)

final results of a noninterventional study

Background Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)–targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. Results In the total population (N = 334), median follow-up was 5.2 months (range, 0–32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5–8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5–9 months) and median PFS was 6.9 months (5–9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. Conclusions This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies (http://www.vfa.de/de/forschung/nisdb/ webcite)

Pharmacokinetic analysis after implantation of everolimus-eluting self-expanding stents in the peripheral vasculature

Background: A novel self-expanding drug-eluting stent was designed to release everolimus 225 mu g/cm(2) to prevent restenosis following peripheral arterial intervention. The purpose of this study was to measure the pharmacokinetic profile of everolimus following stent implantation. Methods: One hundred four patients with symptomatic peripheral arterial disease underwent implantation of everolimus-eluting stents in the femoropopliteal arteries. In a prespecified subset of 26 patients, blood samples for assay of everolimus content were collected prior to stent implantation, at 1, 4, and 8 hours postprocedure, prior to discharge, and at 1 month postproccdure. Results: A total of 39 stents, ranging from 28 mm to 100 mm in length, were implanted in 26 patients, resulting in a total delivered everolimus dose range of 3.0 to 7.6 mg. Following the procedure, the maximum observed everolimus blood concentrations (C-max) varied from 1.83 +/- 0.05 ng/mL after implantation of a single 80-mm stent to 4.66 +/- 1.78 ng/mL after implantation of two 100-mm stents. The mean time to peak concentration (T-max) varied from 6.8 hours to 35 hours. The pharmacokinetics of everolimus were dose-proportional in that dose-normalized C-max and area under the curve values were constant over the studied dose range. Conclusions: After implantation of everolimus-eluting self-expanding stents in the femoropopliteal arteries, systemic blood concentrations of everolimus are predictable and considerably lower than blood concentrations observed following safe oral administration of everolimus