Jiayi Huang1,2, Rekha Chaudhary3, Adam L Cohen4, Karen Fink5, Samuel Goldlust6, John Boockvar7, Prakash Chinnaiyan8, Leping Wan9, Stephen Marcus10, Jian L Campian9. 1. Washington University School of Medicine, St. Louis, MO, USA. jiayi.huang@wustl.edu. 2. Department of Radiation Oncology, Center for Advanced Medicine, Washington University School of Medicine, 4921 Parkview Place, Campus Box #8224, St. Louis, MO, 63110, USA. jiayi.huang@wustl.edu. 3. University of Cincinnati College of Medicine, Cincinnati, OH, USA. 4. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 5. Baylor University Medical Center, Dallas, TX, USA. 6. Hackensack University Medical Center, Hackensack, NJ, USA. 7. Lenox Hill Hospital, New York, NY, USA. 8. Beaumont Health, Royal Oak, MI, USA. 9. Washington University School of Medicine, St. Louis, MO, USA. 10. Cantex Pharmaceuticals, Weston, FL, USA.
Abstract
PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.
PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.
Authors: Karen Jaqueline Paredes-Ruiz; Karla Chavira-Ramos; Mario Orozco-Morales; Cimen Karasu; Alexey A Tinkov; Michael Aschner; Abel Santamaría; Ana Laura Colín-González Journal: Neurotox Res Date: 2021-11-06 Impact factor: 3.911
Authors: Emily J Koubek; Rachel A Kudgus; Chad A Walden; Renee M McGovern; Joseph M Covey; Matthew M Ames; Joel M Reid Journal: Cancer Chemother Pharmacol Date: 2022-07-27 Impact factor: 3.288
Authors: Kristen C Kelley; Kenneth F Grossman; Mary Brittain-Blankenship; Kelli M Thorne; Wallace L Akerley; Moises C Terrazas; Ken M Kosak; Kenneth M Boucher; Saundra S Buys; Kimberly A McGregor; Theresa L Werner; Neeraj Agarwal; John R Weis; Sunil Sharma; John H Ward; Thomas P Kennedy; Douglas W Sborov; Paul J Shami Journal: BMC Cancer Date: 2021-05-07 Impact factor: 4.430