Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma

Abstract

Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500-1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8-8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3-19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.

Targeting genotoxic and proteotoxic stress‐response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram

“…Another intriguing option for future treatment is concomitant DSF (ideally supplemented with copper) with other anticancer drugs or IR. Such combinations show promising results in preclinical models and also in a few clinical trials . In this study, we demonstrated toxicity of the CuET complex, the main anticancer metabolite of disulfiram in vivo as well as potency of DSF in combination with copper.…”

“…Such combinations show promising results in preclinical models 50,51 and also in a few clinical trials. 52,53 In this study, we demonstrated toxicity of the CuET complex, the main anticancer metabolite of disulfiram in vivo 10 as well as potency of DSF in combination with copper. These treatments also induced cellular responses which were reported for other cell lines, including UPR and HSR pathway activation.…”

Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model

“…The toxicity and pharmacodynamic effect of disulfiram have recently been evaluated in humans. The administration of 500 mg disulfiram concurrent with 2 mg copper was well tolerated in patients with glioblastoma (Huang et al 2018). Therefore, oral administration of copper with disulfiram is feasible for patients with MD and further optimization of the dose is anticipated.…”

Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments

“…Meanwhile, rapid exploration in the past decade has provided significant insight not only for understanding the mechanisms of the neoplasm on a molecular basis, but also in designing new anticancer treatments. Therefore, in 2014, the International Society of Neuropathology included molecular information on top of the histological characteristics in brain tumor diagnoses [5][6][7]. This led to substantial modifications to the World Health Organization Classification of Tumors of the CNS (CNS WHO) in 2016 [5,6].…”

“…Aurora kinase inhibitor;2 Nitrosourea, also known as CCNU; 3 Proteasome inhibitor;4 Taxane-derived antineoplastic agent;5 Pan-class I phosphoinositide 3-kinase inhibitor;6 Receptor tyrosine kinase inhibitor;7 Topoisomerase I inhibitor;8 Histone deacetylase inhibitor;9 NMDA receptor inhibitor;10 Phospholipid-interacting antimalarial drug;11 Anti-diabetic drug12 Anti-angiogenic agent;13 Allogeneic/Autologous vaccine; 14 CDK4/6 inhibitor;15 Poly ADP ribose polymerase (PARP) inhibitor;16 Antibody-drug conjugate;17 Third-generation nitrosourea; 18 Wee1 inhibitor;19 Proteasome inhibitor;20 Non-voltage-dependent calcium channel inhibitor;21 Interferon-binding protein;22 Rapamycin (mTOR) inhibitor;23 Raf kinase…”