Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study

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dc.contributor.authorFranz, David Nen_ZA
dc.contributor.authorBelousova, Elenaen_ZA
dc.contributor.authorSparagana, Stevenen_ZA
dc.contributor.authorBebin, E Martinaen_ZA
dc.contributor.authorFrost, Michael Den_ZA
dc.contributor.authorKuperman, Rachelen_ZA
dc.contributor.authorWitt, Olafen_ZA
dc.contributor.authorKohrman, Michael Hen_ZA
dc.contributor.authorFlamini, J Roberten_ZA
dc.contributor.authorWu, Joyce Yen_ZA
dc.contributor.authorCuratolo, Paoloen_ZA
dc.contributor.authorDe Vries, Petrus Jen_ZA
dc.contributor.authorBerkowitz, Noahen_ZA
dc.contributor.authorNiolat, Julieen_ZA
dc.contributor.authorJóźwiak, Sergiuszen_ZA
dc.date.accessioned2016-10-31T07:43:37Z
dc.date.available2016-10-31T07:43:37Z
dc.date.issued2016en_ZA
dc.description.abstractBACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828). Methods and FINDINGS: EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m 2 /day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%). CONCLUSIONS: Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients. Trial Registration ClinicalTrials.gov NCT00789828en_ZA
dc.identifier.apacitationFranz, D. N., Belousova, E., Sparagana, S., Bebin, E. M., Frost, M. D., Kuperman, R., ... Jóźwiak, S. (2016). Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study. <i>PLoS One</i>, http://hdl.handle.net/11427/22376en_ZA
dc.identifier.chicagocitationFranz, David N, Elena Belousova, Steven Sparagana, E Martina Bebin, Michael D Frost, Rachel Kuperman, Olaf Witt, et al "Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study." <i>PLoS One</i> (2016) http://hdl.handle.net/11427/22376en_ZA
dc.identifier.citationFranz, David N., Elena Belousova, Steven Sparagana, E. Martina Bebin, Michael D. Frost, Rachel Kuperman, Olaf Witt et al. "Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study." PLoS One 11, no. 6 (2016): e0158476. doi:10.1371/journal.pone.0158476en_ZA
dc.identifier.ris TY - Journal Article AU - Franz, David N AU - Belousova, Elena AU - Sparagana, Steven AU - Bebin, E Martina AU - Frost, Michael D AU - Kuperman, Rachel AU - Witt, Olaf AU - Kohrman, Michael H AU - Flamini, J Robert AU - Wu, Joyce Y AU - Curatolo, Paolo AU - De Vries, Petrus J AU - Berkowitz, Noah AU - Niolat, Julie AU - Jóźwiak, Sergiusz AB - BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828). Methods and FINDINGS: EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m 2 /day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%). CONCLUSIONS: Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients. Trial Registration ClinicalTrials.gov NCT00789828 DA - 2016 DB - OpenUCT DO - 10.1371/journal.pone.0158476 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 T1 - Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study TI - Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study UR - http://hdl.handle.net/11427/22376 ER - en_ZA
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0158476en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/22376
dc.identifier.vancouvercitationFranz DN, Belousova E, Sparagana S, Bebin EM, Frost MD, Kuperman R, et al. Long-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 study. PLoS One. 2016; http://hdl.handle.net/11427/22376.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Psychiatry and Mental Healthen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2016 Franz et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherLesionsen_ZA
dc.subject.otherHydrocephalusen_ZA
dc.subject.otherCancer treatmenten_ZA
dc.subject.otherPneumoniaen_ZA
dc.subject.otherRadiology and imagingen_ZA
dc.subject.otherAdverse eventsen_ZA
dc.subject.otherMouthen_ZA
dc.subject.otherTuberous sclerosisen_ZA
dc.titleLong-term use of Everolimus in patients with Tuberous Sclerosis Complex: final results from the EXIST-1 studyen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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