Evanthia Galanis1, S Keith Anderson1,2, C Ryan Miller3, Jann N Sarkaria4, Kurt Jaeckle5, Jan C Buckner1, Keith L Ligon6, Karla V Ballman2, Dennis F Moore7, Michael Nebozhyn8, Andrey Loboda9, David Schiff10, Manmeet Singh Ahluwalia11, Eudocia Q Lee12, Elizabeth R Gerstner13, Glenn J Lesser14, Michael Prados15, Stuart A Grossman16, Jane Cerhan17, Caterina Giannini18, Patrick Y Wen12. 1. Department of Oncology, Mayo Clinic, Rochester, Minnesota. 2. Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. 3. Pathobiology and Translational Science Graduate Program, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina. 4. Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. 5. Department of Neurology, Mayo Clinic, Jacksonville, Minnesota. 6. Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. 7. Department of Internal Medicine, Cancer Center of Kansas, Wichita, Kansas. 8. Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, Pennsylvania. 9. Data Analysis, Informatics & Analysis Department, Merck Research Laboratories, Boston, Massachusetts. 10. Neuro-Oncology Center, University of Virginia School of Medicine, Charlottesville, Virginia. 11. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. 12. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 13. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts. 14. Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina. 15. Department of Neurological Surgery, University of California San Francisco, San Francisco, California. 16. Department of Oncology, Medicine & Neurosurgery, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. 17. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota. 18. Department of Pathology, Mayo Clinic, Rochester, Minnesota.
Abstract
Background: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods: Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
Background: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods:Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
Authors: Laurence Booth; Jane L Roberts; Adam Conley; Nichola Cruickshanks; Thomas Ridder; Steven Grant; Andrew Poklepovic; Paul Dent Journal: Cancer Biol Ther Date: 2013-12-18 Impact factor: 4.742
Authors: Hasan C Ugur; Naren Ramakrishna; Lorenzo Bello; Lata G Menon; Seung-Ki Kim; Peter M Black; Rona S Carroll Journal: J Neurooncol Date: 2007-02-20 Impact factor: 4.130
Authors: Thomas Asklund; Samuel Kvarnbrink; Camilla Holmlund; Carl Wibom; Tommy Bergenheim; Roger Henriksson; Håkan Hedman Journal: Anticancer Res Date: 2012-07 Impact factor: 2.480
Authors: Mark R Gilbert; James J Dignam; Terri S Armstrong; Jeffrey S Wefel; Deborah T Blumenthal; Michael A Vogelbaum; Howard Colman; Arnab Chakravarti; Stephanie Pugh; Minhee Won; Robert Jeraj; Paul D Brown; Kurt A Jaeckle; David Schiff; Volker W Stieber; David G Brachman; Maria Werner-Wasik; Ivo W Tremont-Lukats; Erik P Sulman; Kenneth D Aldape; Walter J Curran; Minesh P Mehta Journal: N Engl J Med Date: 2014-02-20 Impact factor: 91.245
Authors: Roger Stupp; Monika E Hegi; Thierry Gorlia; Sara C Erridge; James Perry; Yong-Kil Hong; Kenneth D Aldape; Benoit Lhermitte; Torsten Pietsch; Danica Grujicic; Joachim Peter Steinbach; Wolfgang Wick; Rafał Tarnawski; Do-Hyun Nam; Peter Hau; Astrid Weyerbrock; Martin J B Taphoorn; Chiung-Chyi Shen; Nalini Rao; László Thurzo; Ulrich Herrlinger; Tejpal Gupta; Rolf-Dieter Kortmann; Krystyna Adamska; Catherine McBain; Alba A Brandes; Joerg Christian Tonn; Oliver Schnell; Thomas Wiegel; Chae-Yong Kim; Louis Burt Nabors; David A Reardon; Martin J van den Bent; Christine Hicking; Andriy Markivskyy; Martin Picard; Michael Weller Journal: Lancet Oncol Date: 2014-08-19 Impact factor: 41.316
Authors: Jonathan Dow; Adam Krysztofiak; Yanfeng Liu; Daniel A Colon-Rios; Faye A Rogers; Peter M Glazer Journal: Mol Cancer Res Date: 2021-09-17 Impact factor: 6.333
Authors: Vaidya Govindarajan; Ashish H Shah; Long Di; Sarah Rivas; Robert K Suter; Daniel G Eichberg; Evan Luther; Victor Lu; Alexis A Morell; Michael E Ivan; Ricardo J Komotar; Nagi Ayad; Macarena De La Fuente Journal: World Neurosurg Date: 2022-03-18 Impact factor: 2.210
Authors: Steven G DuBois; M Meaghan Granger; Susan Groshen; Denice Tsao-Wei; Lingyun Ji; Anasheh Shamirian; Scarlett Czarnecki; Fariba Goodarzian; Rachel Berkovich; Hiroyuki Shimada; Judith G Villablanca; Kieuhoa T Vo; Navin Pinto; Yael P Mosse; John M Maris; Suzanne Shusterman; Susan L Cohn; Kelly C Goldsmith; Brian Weiss; Gregory A Yanik; Clare J Twist; Meredith S Irwin; Daphne A Haas-Kogan; Julie R Park; Araz Marachelian; Katherine K Matthay Journal: J Clin Oncol Date: 2021-07-16 Impact factor: 44.544