{Reference Type}: Journal Article
{Title}: A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.
{Author}: Huang J;Campian JL;DeWees TA;Skrott Z;Mistrik M;Johanns TM;Ansstas G;Butt O;Leuthardt E;Dunn GP;Zipfel GJ;Osbun JW;Abraham C;Badiyan S;Schwetye K;Cairncross JG;Rubin JB;Kim AH;Chheda MG;
{Journal}: Int J Radiat Oncol Biol Phys
{Volume}: 0
{Issue}: 0
{Year}: 2024 May 19
{Factor}: 8.013
{DOI}: 10.1016/j.ijrobp.2024.05.009
{Abstract}: <B>OBJECTIVE: </B>This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM).<BR><B>METHODS: </B>Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry.<BR><B>RESULTS: </B>Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors.<BR><B>CONCLUSIONS: </B>The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.