Phase II Results: TMZ with DISULFIRAM and COPPER (SNO 2018)

The disappointing results of this study are published in the SNO 2018 brochure:

http://sci-hub.tw/https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_6/NP/5154662?redirectedFrom=fulltext

"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.

Final results of disulfiram pilot trial for newly diagnosed GBM

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
http://sci-hub.la/https://link.springer.com/article/10.1007/s11060-018-2775-y

Sadly, median PFS and OS were not improved above historical controls receiving standard treatments alone.

However, only 6 of 18 patients also took copper supplements in this trial in addition to disulfiram, leading to another phase 1/2 trial of disulfiram + copper for newly diagnosed GBM which is still recruiting.
https://clinicaltrials.gov/ct2/show/NCT02715609

Disulfiram + copper + radiation + TMZ case report

While not providing definite evidence of disulfiram activity, this case study on the use of disulfiram + copper for an IDH1-mutant, MGMT-unmethylated glioblastoma does show that disulfiram therapy can be initiated at the time of radiation.  The disulfiram dose was 250 mg daily, and the dose of copper gluconate was 3 mg twice daily.

Evidence for the efficacy of disulfiram and copper combinationin glioblastoma multiforme - A propos of a case

New disulfiram trial in Sweden

DIRECT (DIsulfiram REsponse as add-on to ChemoTherapy in Recurrent) Glioblastoma: A Randomized Controlled Trial

This is a randomized phase 2/3 trial with an expected recruitment of 142 patients recruiting in Norway and soon to be recruiting at multiple centers in Sweden.

One arm gets standard alkylating chemotherapy at recurrence, and the other arm gets standard chemotherapy plus disulfiram and copper.

NCT02678975

Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of Glioblastoma.

View study here

This study is exciting as it is the first study of disulfiram + copper in orthotopic GBM patient-derived xenograft mouse models.  Disulfiram and copper were given orally, not by injection, at clinically relevant doses.  The disulfiram + copper had little effect on its own in the mice, but sensitized the tumors to TMZ.  The testing was done on both newly diagnosed and recurrent samples.

Dosing DCA ,Disulfiram together

Please correct me if I am wrong.

So both Disulfiram and DCA cause neuropathy. I am trying to dose both.

DCA can cause memory problems and hand tremors and possible Korsakoffs syndrome which could be very serious and what  I am worried the most about. Of all the patients treated by Medicore they did not mention that side effect of DCA but in theory it is possible.

So this Korsakoffs is caused by not enough vit B1. 

Neuropathy caused by Disulfiram is caused by other mechanism  I assume and not by vit B1 depletion. CUSP 9 doctors are not supplementing with B1. 

In that case Disulfiram would never cause Krsakoffs or memory problems because it does not deplete vit B1. So dosing Disulfiram even if taken with DCA I wouldn't have to worry about heart failure, or memory problems. So even If vit b1 is low and I stopped DCA I can still give Disulfiram. Is that correct?

Disulfiram and copper

Steven

Do you know what dose of copper would be used with disulfiram?  Being copper seems to be involved in cancer growth if not initation, it seems that the lowest dose of copper should be used.

Also, I am of the belief that it is the copper that is beneficial, not the gluconate component (the study specified CU gluconate)  Typically we see various chelated forms of minerals have different bioavailabitly, but it is the mineral with the therapeutic effect.  In the disulfiram/copper combination I suspect this is the case as well.  Do you know if there is something special about this particular copper preparation that gives it synergy with disulfiram?

Copper and disulfiram in mouse GBM model

A Chinese study just published shows that in a U87 GBM mouse model,  mice given intravenous disulfiram alone had only minor therapeutic benefits, while the mice given intravenous disulfiram plus copper (by stomach) had significantly increased therapeutic benefit, including reduced microvessel density and tumor volume (see figure 8).  I've uploaded this study to the Brain Tumor Library.

There has been considerable debate whether additional copper beyond what is already in the stomach or bloodstream is required to potentiate the anti-cancer effect of disulfiram.  Several mouse studies including the one above have shown that orally delivered copper in mice increases the therapeutic effects of disulfiram.  The original CUSP9 protocol has dosing information on copper gluconate.

Please note that the addition of copper likely also increases the risk of unwanted side-effects such as peripheral neuropathy (see second study below).

Copper improves the anti-angiogenic activity of disulfiram through the EGFR/src/VEGF pathway in gliomas

N,N-Diethyldithiocarbamate Produces Copper Accumulation, Lipid Peroxidation, and Myelin Injury in Rat Peripheral Nerve

Both of these studies may be found in the Library.