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

Jiayi Huang, Jian L. Campian, Amit D. Gujar, Christina Tsien, George Ansstas, David D. Tran, Todd A. DeWees, Albert Lockhart, Albert H. Kim

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)105-111
Number of pages7
JournalJournal of Neuro-Oncology
Volume138
Issue number1
DOIs
StatePublished - May 1 2018
Externally publishedYes

Fingerprint

temozolomide
Disulfiram
Glioblastoma
Copper
Proteasome Endopeptidase Complex
Maximum Tolerated Dose
Chemoradiotherapy

Keywords

  • Copper
  • Disulfiram
  • Glioblastoma
  • Phase 1 study
  • Proteasome inhibition
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

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. / Huang, Jiayi; Campian, Jian L.; Gujar, Amit D.; Tsien, Christina; Ansstas, George; Tran, David D.; DeWees, Todd A.; Lockhart, Albert; Kim, Albert H.

In: Journal of Neuro-Oncology, Vol. 138, No. 1, 01.05.2018, p. 105-111.

Research output: Contribution to journalArticle

Huang, Jiayi ; Campian, Jian L. ; Gujar, Amit D. ; Tsien, Christina ; Ansstas, George ; Tran, David D. ; DeWees, Todd A. ; Lockhart, Albert ; Kim, Albert H. / 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. In: Journal of Neuro-Oncology. 2018 ; Vol. 138, No. 1. pp. 105-111.
@article{efa502803e834b16aaf19e702c85009e,
title = "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.",
keywords = "Copper, Disulfiram, Glioblastoma, Phase 1 study, Proteasome inhibition, Temozolomide",
author = "Jiayi Huang and Campian, {Jian L.} and Gujar, {Amit D.} and Christina Tsien and George Ansstas and Tran, {David D.} and DeWees, {Todd A.} and Albert Lockhart and Kim, {Albert H.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1007/s11060-018-2775-y",
language = "English (US)",
volume = "138",
pages = "105--111",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "1",

}

TY - JOUR

T1 - 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

AU - Huang, Jiayi

AU - Campian, Jian L.

AU - Gujar, Amit D.

AU - Tsien, Christina

AU - Ansstas, George

AU - Tran, David D.

AU - DeWees, Todd A.

AU - Lockhart, Albert

AU - Kim, Albert H.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - Copper

KW - Disulfiram

KW - Glioblastoma

KW - Phase 1 study

KW - Proteasome inhibition

KW - Temozolomide

UR - http://www.scopus.com/inward/record.url?scp=85041115403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041115403&partnerID=8YFLogxK

U2 - 10.1007/s11060-018-2775-y

DO - 10.1007/s11060-018-2775-y

M3 - Article

C2 - 29374809

AN - SCOPUS:85041115403

VL - 138

SP - 105

EP - 111

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

IS - 1

ER -