PMID- 27351628 OWN - NLM STAT- MEDLINE DCOM- 20170724 LR - 20220331 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 6 DP - 2016 TI - Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study. PG - e0158476 LID - 10.1371/journal.pone.0158476 [doi] LID - e0158476 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/m2/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. FAU - Franz, David N AU - Franz DN AD - Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America. FAU - Belousova, Elena AU - Belousova E AD - Department of Pediatrics, Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia. FAU - Sparagana, Steven AU - Sparagana S AD - Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas, United States of America. FAU - Bebin, E Martina AU - Bebin EM AD - Department of Neurology, University of Alabama School of Medicine, Birmingham, Alabama, United States of America. FAU - Frost, Michael D AU - Frost MD AD - Department of Neurology, Minnesota Epilepsy Group, St. Paul, Minnesota, United States of America. FAU - Kuperman, Rachel AU - Kuperman R AD - Department of Neurology, Children's Hospital and Research Center, Oakland, California, United States of America. FAU - Witt, Olaf AU - Witt O AD - Department of Oncology, University of Heidelberg Medical Center and German Cancer Research Center, Heidelberg, Germany. FAU - Kohrman, Michael H AU - Kohrman MH AD - Department of Neurology, University of Chicago, Chicago, Illinois, United States of America. FAU - Flamini, J Robert AU - Flamini JR AD - Department of Neurology, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America. FAU - Wu, Joyce Y AU - Wu JY AD - Department of Neurology, Mattel Children's Hospital at the University of California Los Angeles, Los Angeles, California, United States of America. FAU - Curatolo, Paolo AU - Curatolo P AD - Department of Neurology, University of Rome Tor Vergata, Rome, Italy. FAU - de Vries, Petrus J AU - de Vries PJ AD - Department of Psychiatry and Mental Health, Division of Child & Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa. FAU - Berkowitz, Noah AU - Berkowitz N AD - Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America. FAU - Niolat, Julie AU - Niolat J AD - Department of Oncology, Novartis Pharmaceuticals S.A.S., Rueil-Malmaison, France. FAU - Jozwiak, Sergiusz AU - Jozwiak S AD - Department of Pediatric Neurology, Medical University of Warsaw, Warsaw, Poland. LA - eng SI - ClinicalTrials.gov/NCT00789828 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20160628 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adolescent MH - Antineoplastic Agents/administration & dosage/adverse effects/*therapeutic use MH - Child MH - Child, Preschool MH - Double-Blind Method MH - Everolimus/administration & dosage/adverse effects/*therapeutic use MH - Female MH - Humans MH - Male MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/*therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Tuberous Sclerosis/*drug therapy PMC - PMC4924870 COIS- Competing Interests: Dr. Franz received support from Novartis for other research at his institution, was consultant to Novartis (payments to employer CCHMC), received honoraria from Novartis and Lundbeck Pharmaceuticals, has been reimbursed by Novartis and Lundbeck Pharmaceuticals for travel costs for lectures, and performed legal work in reviewing medical malpractice cases, occasionally in giving expert testimony for various attorneys. Dr. Belousova received honoraria as speaker from Novartis and served as principal investigator on 2 research studies funded by Novartis Oncology. Dr. Sparagana received honoraria as a speaker for Novartis, served as site principal investigator on this and another research study funded by Novartis Oncology, serves on professional advisory board of Tuberous Sclerosis Alliance (TSA), and has received travel funds from the TSA related to role on the TSC Natural History Database Steering Committee. Drs. Bebin, Kuperman, Witt, and Flamini served as principal investigators on a research study funded by Novartis Oncology. Dr. Frost served as a consultant and participated in Advisory Boards for Novartis. Dr. Wu serves on the professional advisory board for the Tuberous Sclerosis Alliance, received honoraria from, serves on the scientific advisory board and the speakers' bureau for Novartis and Lundbeck, and received research support from the Tuberous Sclerosis Alliance, Novartis, Today's and Tomorrow's Children Fund, Department of Defense/Congressionally Directed Medical Research Program, and the National Institutes of Health. Dr. Curatolo received honoraria for serving on advisory boards and providing lectures on behalf of Novartis Oncology. Dr. de Vries served as a consultant and participated in Advisory Boards for Novartis and received travel honoraria from Novartis (donated to charity). Dr. Berkowitz and Ms. Niolat are employees of Novartis. Dr. Jozwiak received honoraria for serving on advisory boards and providing lectures on behalf of Novartis Oncology. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. EDAT- 2016/06/29 06:00 MHDA- 2017/07/25 06:00 PMCR- 2016/06/28 CRDT- 2016/06/29 06:00 PHST- 2016/02/03 00:00 [received] PHST- 2016/06/15 00:00 [accepted] PHST- 2016/06/29 06:00 [entrez] PHST- 2016/06/29 06:00 [pubmed] PHST- 2017/07/25 06:00 [medline] PHST- 2016/06/28 00:00 [pmc-release] AID - PONE-D-15-55575 [pii] AID - 10.1371/journal.pone.0158476 [doi] PST - epublish SO - PLoS One. 2016 Jun 28;11(6):e0158476. doi: 10.1371/journal.pone.0158476. eCollection 2016.