A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma
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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 phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ.
This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (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 survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety.
From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1–12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase).
Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.
KeywordsRecurrent glioblastoma Disulfiram Temozolomide Copper Clinical trial
The study was supported by Cantex Pharmaceuticals. We thank Drs. Josh Rubin and David Warren for their helpful suggestions and review of the manuscript. We also thank all the patients and their families, as well as all the investigators and study teams, for their contribution to the study.
This study was supported by Cantex Pharmaceuticals.
Compliance with ethical standards
Conflict of interest
JH reports research support from Cantex Pharmaceuticals for the submitted work as well as research support from Pfizer for topics outside this work. SG reports consultant fees and Speaker’s honoraria from Wex Pharma and Novocure, outside of the submitted work.
- 1.Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708. https://doi.org/10.1056/NEJMoa1308573 CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31(32):4085–4091. https://doi.org/10.1200/JCO.2013.49.6968 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740. https://doi.org/10.1200/JCO.2008.19.8721 CrossRefPubMedGoogle Scholar
- 5.Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745. https://doi.org/10.1200/JCO.2008.16.3055 CrossRefPubMedGoogle Scholar
- 6.Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ (2017) Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 377(20):1954–1963. https://doi.org/10.1056/NEJMoa1707358 CrossRefPubMedGoogle Scholar
- 8.Liu P, Brown S, Goktug T, Channathodiyil P, Kannappan V, Hugnot JP, Guichet PO, Bian X, Armesilla AL, Darling JL, Wang W (2012) Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer 107(9):1488–1497. https://doi.org/10.1038/bjc.2012.442 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Triscott J, Lee C, Hu K, Fotovati A, Berns R, Pambid M, Luk M, Kast RE, Kong E, Toyota E, Yip S, Toyota B, Dunn SE (2012) Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. Oncotarget 3(10):1112–1123CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Lun X, Wells JC, Grinshtein N, King JC, Hao X, Dang NH, Wang X, Aman A, Uehling D, Datti A, Wrana JL, Easaw JC, Luchman A, Weiss S, Cairncross JG, Kaplan DR, Robbins SM, Senger DL (2016) Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-15-1798 CrossRefPubMedGoogle Scholar
- 13.Nechushtan H, Hamamreh Y, Nidal S, Gotfried M, Baron A, Shalev YI, Nisman B, Peretz T, Peylan-Ramu N (2015) A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist 20(4):366–367. https://doi.org/10.1634/theoncologist.2014-0424 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Huang J, Campian JL, Gujar AD, Tran DD, Lockhart AC, DeWees TA, Tsien CI, Kim AH (2016) A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy. J Neurooncol 128(2):259–266. https://doi.org/10.1007/s11060-016-2104-2 CrossRefPubMedGoogle Scholar
- 15.Huang J, Campian JL, Gujar AD, Tsien C, Ansstas G, Tran DD, DeWees TA, Lockhart AC, Kim AH (2018) 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. J Neurooncol. https://doi.org/10.1007/s11060-018-2775-y CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncoln Oncol 28(11):1963–1972. https://doi.org/10.1200/JCO.2009.26.3541 CrossRefGoogle Scholar
- 17.Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE II, Walker A, Friedman HS (2009) Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol 27(8):1262–1267. https://doi.org/10.1200/JCO.2008.18.8417 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Raynal NJ, Lee JT, Wang Y, Beaudry A, Madireddi P, Garriga J, Malouf GG, Dumont S, Dettman EJ, Gharibyan V, Ahmed S, Chung W, Childers WE, Abou-Gharbia M, Henry RA, Andrews AJ, Jelinek J, Cui Y, Baylin SB, Gill DL, Issa JP (2016) Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer. Cancer Res 76(6):1494–1505. https://doi.org/10.1158/0008-5472.CAN-14-2391 CrossRefPubMedGoogle Scholar