The disappointing results of this study are published in the SNO 2018 brochure:
"ACTR-19. A MULTICENTER PILOT PHASE II STUDY OF
CONTINUING TMZ WITH THE ADDITION OF DISULFIRAM AND
COPPER FOR REFRACTORY GLIOBLASTOMA"
BACKGROUND: 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 pilot phase II study
aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize
recurrent GBM to TMZ. METHOD: This open-label, single-arm phase
II study treated recurrent TMZ-refractory GBM patients with TMZ
150mg/m2 on days 1–5 of every 28-day cycle with concurrent daily DSF
80mg TID and Cu 1.5mg TID. Eligible patients must have progressed
after standard chemoradiotherapy and within 3 months of the last dose
of TMZ. Known 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 (OS), clinical benefit (stable disease for at least 6 months), and safety.
Evaluable patients must have received at least 28 days of DSF/Cu unless
stopped due to progression, toxicity, or death.
RESULTS: From March
2017 to January 2018, 23 TMZ-refractory GBM patients were enrolled
across seven centers in the United States, and 22 patients were evaluable.
The median DSF/Cu duration was 48 days (range: 12–246 days). After a
median follow-up of 4.4 months, there were no objective responses, with
6-month PFS of 14% and 6-month OS of 55%. Among 17 patients who
had at least 28 days of DSF/Cu, 3 patients (18%) had clinical benefit.
Grade 3 toxicities that were possibly related to DFS/Cu included fatigue,
headache, anxiety, and elevated alanine transaminase (5% for each).
CONCLUSION: Addition of DSF/Cu to TMZ for TMZ-refractory GBM
yielded minimal ORR but demonstrated clinical benefit for a subset of
patients. DSF/Cu may have modest TMZ re-sensitization or single-agent
activity for recurrent GBM.
It's disappointing, but the dosing seems low to me. 80 mg three times daily = 240 mg disulfiram per day. I would have doubled that to 500 mg or more on the week surrounding TMZ.
ReplyDeleteThere are several more disulfiram trials in GBM either planned or recruiting, so the story of disulfiram for GBM is not over yet. Perhaps a different dosing schedule or use in newly diagnosed disease will be more beneficial.
https://clinicaltrials.gov/ct2/show/NCT03363659
https://clinicaltrials.gov/ct2/show/NCT02678975
https://clinicaltrials.gov/ct2/show/NCT02715609
https://clinicaltrials.gov/ct2/show/NCT01777919