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28-06-2022 | Research

Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial

Authors: M Mego, D Svetlovska, De Angelis V, K Kalavska, P Lesko, M Makovník, J Obertova, Z Orszaghova, P Palacka, M Rečková, K Rejlekova, Sycova-Mila Z, J Mardiak, M Chovanec

Published in: Investigational New Drugs | Issue 5/2022

Abstract

Background

Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs.

Methods

Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m² day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report.

Results

Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1–6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7–1.5 months), and median overall survival was 2.9 months 95% CI (1.5–4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection.

Conclusions

This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.

Einhorn LH (1990) Treatment of testicular cancer: a new and improved model. J Clin Oncol 8(11):1777–1781. doi:https://doi.org/10.1200/JCO.1990.8.11.1777CrossRefPubMed

Lorch A, Kleinhans A, Kramar A, Kollmannsberger CK, Hartmann JT, Bokemeyer C, Rick O, Beyer J (2012) Sequential versus single high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: long-term results of a prospective randomized trial. J Clin Oncol 30(8):800–805. doi:https://doi.org/10.1200/JCO.2011.38.6391CrossRefPubMed

Kondagunta GV, Bacik J, Donadio A, Bajorin D, Marion S, Sheinfeld J, Bosl GJ, Motzer RJ (2005) Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 23(27):6549–6555. doi:https://doi.org/10.1200/JCO.2005.19.638CrossRefPubMed

Mardiak J, Salek T, Sycova-Mila Z, Obertova J, Hlavata Z, Mego M, Reckova M, Koza I (2005) Paclitaxel plus ifosfamide and cisplatin in second-line treatment of germ cell tumors: a phase II study. Neoplasma 52(6):497–501PubMed

Mead GM, Cullen MH, Huddart R, Harper P, Rustin GJ, Cook PA, Stenning SP, Mason M, Party MRCTTW (2005) A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial. Br J Cancer 93(2):178–184. doi:https://doi.org/10.1038/sj.bjc.6602682CrossRefPubMedPubMedCentral

Kollmannsberger C, Nichols C, Bokemeyer C (2006) Recent advances in management of patients with platinum-refractory testicular germ cell tumors. Cancer 106(6):1217–1226. doi:https://doi.org/10.1002/cncr.21742CrossRefPubMed

Feldman DR, Patil S, Trinos MJ, Carousso M, Ginsberg MS, Sheinfeld J, Bajorin DF, Bosl GJ, Motzer RJ (2012) Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design. Cancer 118(4):981–986. doi:https://doi.org/10.1002/cncr.26375CrossRefPubMed

Necchi A, Nicolai N, Mariani L, Lo Vullo S, Giannatempo P, Raggi D, Fare E, Piva L, Biasoni D, Catanzaro M, Torelli T, Stagni S, Milani A, Gianni AM, Salvioni R (2014) Combination of paclitaxel, cisplatin, and gemcitabine (TPG) for multiple relapses or platinum-resistant germ cell tumors: long-term outcomes. Clin Genitourin Cancer 12(1):63–69e61. doi:https://doi.org/10.1016/j.clgc.2013.07.005CrossRefPubMed

De Ugo GS, Gurioli G, Pisano C, Basso U, Lolli C, Petracci E, Casadei C, Cecere SC, Attademo L, Clemente A, Zampiga V, Galla V Ilaria Cangini, Marilena Di Napoli, Linda Valmorri, Sandro Pignata (2020) Olaparib as salvage treatment for advanced germ cell tumors after chemotherapy failure: Results of the open-label, single-arm, IGG-02 phase II trial.Journal of Clinical Oncology38 (No. 15_suppl):5058–5058. doi: https://doi.org/10.1200/JCO.2020.38.15_suppl.5058

10.

Mego M, Svetlovska D, Reckova M, Angelis, Kalavska K, Obertova J, Palacka P, Rejlekova K, Sycova-Mila Z, Chovanec M, Mardiak J (2021) Gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumours: The GCT-SK-004 phase II trial. Invest New Drugs 39(6):1664–1670. doi:https://doi.org/10.1007/s10637-021-01130-5CrossRefPubMed

11.

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567. doi:https://doi.org/10.1016/j.stem.2007.08.014CrossRefPubMedPubMedCentral

12.

Zhao J (2016) Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacol Ther 160:145–158. doi:https://doi.org/10.1016/j.pharmthera.2016.02.008CrossRefPubMedPubMedCentral

13.

Reuben JM, Lee BN, Gao H, Cohen EN, Mego M, Giordano A, Wang X, Lodhi A, Krishnamurthy S, Hortobagyi GN, Cristofanilli M, Lucci A, Woodward WA (2011) Primary breast cancer patients with high risk clinicopathologic features have high percentages of bone marrow epithelial cells with ALDH activity and CD44(+)CD24lo cancer stem cell phenotype. Eur J Cancer 47(10):1527–1536. doi:https://doi.org/10.1016/j.ejca.2011.01.011CrossRefPubMedPubMedCentral

14.

Zhou L, Sheng D, Wang D, Ma W, Deng Q, Deng L, Liu S (2019) Identification of cancer-type specific expression patterns for active aldehyde dehydrogenase (ALDH) isoforms in ALDEFLUOR assay. Cell Biol Toxicol 35(2):161–177. doi:https://doi.org/10.1007/s10565-018-9444-yCrossRefPubMed

15.

Schmidtova S, Dorssers LCJ, Kalavska K, Gillis AJM, Oosterhuis JW, Stoop H, Miklikova S, Kozovska Z, Burikova M, Gercakova K, Durinikova E, Chovanec M, Mego M, Kucerova L, Looijenga LHJ (2020) Napabucasin overcomes cisplatin resistance in ovarian germ cell tumor-derived cell line by inhibiting cancer stemness. Cancer Cell Int 20:364. doi:https://doi.org/10.1186/s12935-020-01458-7CrossRefPubMedPubMedCentral

16.

Schmidtova S, Kalavska K, Gercakova K, Cierna Z, Miklikova S, Smolkova B, Buocikova V, Miskovska V, Durinikova E, Burikova M, Chovanec M, Matuskova M, Mego M, Kucerova L (2019) Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells. Cancers (Basel) 11(9). doi:https://doi.org/10.3390/cancers11091224

17.

Kleczkowska P, Sulejczak D, Zaremba M (2021) Advantages and disadvantages of disulfiram coadministered with popular addictive substances. Eur J Pharmacol 904:174143. doi:https://doi.org/10.1016/j.ejphar.2021.174143CrossRefPubMed

18.

MacDonagh L, Gallagher MF, Ffrench B, Gasch C, Breen E, Gray SG, Nicholson S, Leonard N, Ryan R, Young V, O’Leary JJ, Cuffe S, Finn SP, O’Byrne KJ, Barr MP (2017) Targeting the cancer stem cell marker, aldehyde dehydrogenase 1, to circumvent cisplatin resistance in NSCLC. Oncotarget 8(42):72544–72563. doi:https://doi.org/10.18632/oncotarget.19881CrossRefPubMedPubMedCentral

19.

Kadia AR, Shah GB (2016) Cisplatin resistance reversal by disulfiram and caffeine. J Pharmacol Pharmacother 7(3):139–141. doi:https://doi.org/10.4103/0976-500X.189676CrossRefPubMedPubMedCentral

20.

O’Brien A, Barber JE, Reid S, Niknejad N, Dimitroulakos J (2012) Enhancement of cisplatin cytotoxicity by disulfiram involves activating transcription factor 3. Anticancer Res 32(7):2679–2688PubMed

21.

Wang NN, Wang LH, Li Y, Fu SY, Xue X, Jia LN, Yuan XZ, Wang YT, Tang X, Yang JY, Wu CF (2018) Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. Exp Cell Res 362(1):72–82. doi:https://doi.org/10.1016/j.yexcr.2017.11.004CrossRefPubMed

22.

Huang J, Chaudhary R, Cohen AL, Fink K, Goldlust S, Boockvar J, Chinnaiyan P, Wan L, Marcus S, Campian JL (2019) A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma. J Neurooncol 142(3):537–544. doi:https://doi.org/10.1007/s11060-019-03125-yCrossRefPubMed

23.

Kelley KC, Grossman KF, Brittain-Blankenship M, Thorne KM, Akerley WL, Terrazas MC, Kosak KM, Boucher KM, Buys SS, McGregor KA, Werner TL, Agarwal N, Weis JR, Sharma S, Ward JH, Kennedy TP, Sborov DW, Shami PJ (2021) A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker. BMC Cancer 21(1):510. doi:https://doi.org/10.1186/s12885-021-08242-4CrossRefPubMedPubMedCentral

24.

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. doi:https://doi.org/10.1634/theoncologist.2014-0424CrossRefPubMedPubMedCentral

25.

Verma S, Stewart DJ, Maroun JA, Nair RC (1990) A randomized phase II study of cisplatin alone versus cisplatin plus disulfiram. Am J Clin Oncol 13(2):119–124CrossRef

26.

Stewart DJ, Verma S, Maroun JA (1987) Phase I study of the combination of disulfiram with cisplatin. Am J Clin Oncol 10(6):517–519CrossRef

27.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRef

28.

Mego M, Svetlovska D, Chovanec M, Reckova M, Rejlekova K, Obertova J, Palacka P, Sycova-Mila Z, De Giorgi U, Mardiak J (2019) Phase II study of avelumab in multiple relapsed/refractory germ cell cancer. Invest New Drugs 37(4):748–754. doi:https://doi.org/10.1007/s10637-019-00805-4CrossRefPubMed

29.

Mego M, Svetlovska D, Miskovska V, Obertova J, Palacka P, Rajec J, Sycova-Mila Z, Chovanec M, Rejlekova K, Zuzak P, Ondrus D, Spanik S, Reckova M, Mardiak J (2016) Phase II study of everolimus in refractory testicular germ cell tumors. Urol Oncol 34(3):122e117–122e122. doi:https://doi.org/10.1016/j.urolonc.2015.10.010CrossRef

30.

De Giorgi U, Rosti G, Aieta M, Testore F, Burattini L, Fornarini G, Naglieri E, Lo Re G, Zumaglini F, Marangolo M (2006) Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol 50 (5):1032–1038; discussion 1038–1039. doi:https://doi.org/10.1016/j.eururo.2006.05.011

31.

Kannappan V, Ali M, Small B, Rajendran G, Elzhenni S, Taj H, Wang W, Dou QP (2021) Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents. Front Mol Biosci 8:741316. doi:https://doi.org/10.3389/fmolb.2021.741316CrossRefPubMedPubMedCentral

32.

Timmerman DM, Eleveld TF, Sriram S, Dorssers LCJ, Gillis AJM, Schmidtova S, Kalavska K, van de Werken HJG, Oing C, Honecker F, Mego M, Looijenga LHJ (2022) Chromosome 3p25.3 Gain Is Associated With Cisplatin Resistance and Is an Independent Predictor of Poor Outcome in Male Malignant Germ Cell Tumors. J Clin Oncol:JCO2102809. doi:https://doi.org/10.1200/JCO.21.02809CrossRef

Title: Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial
Authors: M Mego
D Svetlovska
De Angelis V
K Kalavska
P Lesko
M Makovník
J Obertova
Z Orszaghova
P Palacka
M Rečková
K Rejlekova
Sycova-Mila Z
J Mardiak
M Chovanec
Publication date: 28-06-2022
Publisher: Springer US
Published in: Investigational New Drugs / Issue 5/2022
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-022-01271-1

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