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Role of Chemotherapy, VEGFR Inhibitors, and mTOR Inhibitors in Advanced Perivascular Epithelioid Cell Tumors (PEComas).
Sanfilippo, R, Jones, RL, Blay, JY, Le Cesne, A, Provenzano, S, Antoniou, G, Mir, O, Fucà, G, Fumagalli, E, Bertulli, R, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;(17):5295-5300
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Abstract
PURPOSE Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas. EXPERIMENTAL DESIGN This was an observational, retrospective, international study that included patients with advanced/metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models. RESULTS A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens [objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months] seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months. CONCLUSIONS Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.
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A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer.
Wainberg, ZA, Alsina, M, Soares, HP, Braña, I, Britten, CD, Del Conte, G, Ezeh, P, Houk, B, Kern, KA, Leong, S, et al
Targeted oncology. 2017;(6):775-785
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Abstract
BACKGROUND This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. OBJECTIVES Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. PATIENTS AND METHODS Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D. RESULTS The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations. CONCLUSIONS Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.
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Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial.
Nashan, B, Schemmer, P, Braun, F, Dworak, M, Wimmer, P, Schlitt, H
Trials. 2015;:118
Abstract
BACKGROUND Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients. METHODS/DESIGN Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis. DISCUSSION This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus. TRIAL REGISTRATION NCT01551212 .
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Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.
Gomez-Martin, C, Bustamante, J, Castroagudin, JF, Salcedo, M, Garralda, E, Testillano, M, Herrero, I, Matilla, A, Sangro, B
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2012;(1):45-52
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There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.
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Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.
Woillard, JB, Kamar, N, Rousseau, A, Rostaing, L, Marquet, P, Picard, N
Pharmacogenetics and genomics. 2012;(10):725-32
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Abstract
BACKGROUND The mammalian target of rapamycin (m-TOR) inhibitor sirolimus is an immunosuppressive drug used in kidney transplantation. m-TOR binds with Raptor and phosphorylates p70S6 kinase, a protein involved in numerous cell signalling pathways. We examined the association of candidate polymorphisms in m-TOR, Raptor and p70S6K, sirolimus dose and exposure, and other time-independent as well as time-dependent covariates, with sirolimus-induced adverse events in kidney transplant recipients. METHODS This study included a first group of 113 patients, switched from a calcineurin inhibitor to sirolimus, and a validation group of 66 patients from another clinical trial, with the same immunosuppressive regimen. The effects of gene polymorphisms and covariates on the total cholesterol, LDL cholesterol, triglycerides, haemoglobin, cutaneous adverse events, oedemas and infections were studied using multilinear regression, or logistic regression imbedded in linear mixed-effect models. RESULTS An m-TOR variant haplotype was significantly associated with a decrease in haemoglobin levels in the two populations of patients (discovery group: β=-0.82 g/dl, P=0.0076; validation group: β=-1.58 g/dl, P=0.0308). Increased sirolimus trough levels were significantly associated with increased total cholesterol levels (discovery group: β=0.02 g/l, P<0.0001; validation group: β=0.02 g/l, P=0.0002) and triglyceride levels (discovery group: β=0.02 g/l, P=0.0059; validation group: β=0.05 g/l, P=0.0370). Sirolimus trough levels were also associated with an increased risk for cutaneous adverse events [odds ratio=1.97, 95% confidence interval (1.32-1.94), P=0.0009] and oedemas [odds ratio=1.16, 95% confidence interval (1.03-1.30), P=0.01342] in the discovery group, but this was not confirmed in the validation group. CONCLUSION These results provide evidence of an association between an m-TOR haplotype and a decrease in haemoglobin in renal transplant recipients.
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[Third-line therapy for metastasized renal cell carcinoma: a randomized, multicenter non-blinded phase III study to compare safety and effectiveness of TF1258 versus sorafenib in patients with metastasized renal cell carcinoma following failure of antiangiogenic (VEGF targeted and mTOR inhibition) therapy (GOLD-AN 31/11 of the Working Group Urological Oncology)].
Rexer, H
Der Urologe. Ausg. A. 2011;(10):1319-21
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Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial.
Budde, K, Becker, T, Arns, W, Sommerer, C, Reinke, P, Eisenberger, U, Kramer, S, Fischer, W, Gschaidmeier, H, Pietruck, F, et al
Lancet (London, England). 2011;(9768):837-47
Abstract
BACKGROUND Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation. Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy. METHODS In the ZEUS multicentre, open-label study, 503 patients (aged 18-65 years) who had received de-novo kidney transplants were enrolled. After initial treatment with ciclosporin, based on trough concentrations, and enteric-coated mycophenolate sodium (1440 mg/day, orally), corticosteroids (≥5 mg/day prednisolone or equivalent, orally), and basiliximab induction (20 mg, intravenously, on day 0 [2 h before transplantation], and on day 4), 300 (60%) patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6-10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids), or continue standard ciclosporin-based treatment. Randomisation was done by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers. The primary objective was to show better renal function (glomerular filtration rate [GFR]; Nankivell formula) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00154310. FINDINGS 118 (76%) of 155 everolimus-treated patients and 117 (81%) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation. At this timepoint, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen (71·8 mL/min per 1·73 m(2) vs 61·9 mL/min per 1·73 m(2), respectively; mean difference 9·8 mL/min per 1·73 m(2), 95% CI -12·2 to -7·5). Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after randomisation (15 [10%] of 154 vs five [3%] of 146; p = 0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Compared with the ciclosporin regimen, higher mean lipid concentrations, slightly increased urinary protein excretion, and lower haemoglobin concentrations were noted with the everolimus regimen; thrombocytopenia, aphthous stomatitis, and diarrhoea also occurred more often in the everolimus group. A higher incidence of hyperuricaemia was noted with ciclosporin. INTERPRETATION Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients. FUNDING Novartis Pharma.