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

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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.

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Abbreviations

AFP:

alpha-fetoprotein

ECOG:

Eastern cooperative oncology group

HCG:

human chorionic gonadotropin

IGCCCG:

International Germ Cell Cancer Collaborative Group

LDH:

lactate dehydrogenase

LN:

lymph nodes

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Acknowledgements

We would like to acknowledge Dr. Miskovska V for their collaboration and Jancikova A, Krieschova A, Turnova S, Gombarova V and Pekova Z for providing administrative support and Notova D for monitoring.

Funding

This work was supported by the Scientific Grant Agency of the Ministry of Education (Project No. VEGA 1/0349/21), grant of Ministry of Education (Project number MZ SR 2018/39-LFUK-13) and by the Slovak Research and Development Agency (Project number APVV-20-0158).

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Authors and Affiliations

  1. Translational Research Unit, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia

    M Mego, D Svetlovska & K Kalavska

  2. 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10, Bratislava, Slovakia

    M Mego, P Lesko, M Makovník, J Obertova, Z Orszaghova, P Palacka, K Rejlekova, J Mardiak & M Chovanec

  3. National Cancer Institute, Bratislava, Slovakia

    M Mego, D Svetlovska, De Angelis V, K Kalavska, J Obertova, P Palacka, M Rečková, K Rejlekova, Sycova-Mila Z, J Mardiak & M Chovanec

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  1. M Mego
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Contributions

M-M J-M and M.CH participated in the conception and design of this study. D-S and M-R participated in data validation, M-Ma, V-DA, K-K, P-L, J-O, Z-O, P-P, K-R, Z-SM, and M-CH acquired, analyzed and interpreted the data. M-M drafted the article, and all the authors reviewed it critically for its important intellectual content.

Corresponding author

Correspondence to M Mego.

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All the procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent Informed consent was obtained from all individual participants included in the study.

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Mego, M., Svetlovska, D., Angelis V, D. et al. Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial. Invest New Drugs 40, 1080–1086 (2022). https://doi.org/10.1007/s10637-022-01271-1

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