Disulfiram and Cisplatin in Refractory TGCTs.

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Brief Title

Disulfiram and Cisplatin in Refractory TGCTs.

Official Title

Phase II Study of Disulfiram and Cisplatin in Refractory TGCTs.

Brief Summary

      Non-randomized, open-label, single center trial to assess efficacy (as measured by overall
      response rate (ORR) by RECIST 1.1 of disulfiram and cisplatin in patients with multiple
      relapsed/refractory germ cell tumors (GCTs).

Detailed Description

      Germ-cell tumours (GCTs) are extraordinarily chemosensitive and resemble the clinical and
      biological characteristics of a model for the cure of cancer. Nonetheless, a small proportion
      of patients do not have a durable complete remission (CR) with initial chemotherapy. Only
      20-40% of them will be cured with the use of platinum-containing standard-dose or high-dose
      salvage chemotherapy with autologous stem cell transplantation (ASCT). Patients who fail to
      be cured after second-line salvage therapy have an extremely poor prognosis and long term
      survival had been documented in <5%. Paclitaxel plus ifosfamide and cisplatin is considered
      as a standard salvage chemotherapy in relapsed good prognosis GCTs, however, up to 40% of
      favourable prognosis patients failed to achieve durable response to this combination, and
      therefore new treatment strategies are warranted.

      Previously, it was showed that cisplatin resistant TGCTs overexpress ALDH isoforms and
      inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin
      sensitivity. Cisplatin-resistant TGCTs exhibited increased sensitivity to ALDH inhibitor
      disulfiram in vitro. Although Disulfiram (Antabuse) is an approved drug to support the
      treatment of chronic alcoholism, it may serve as an antitumor agent suitable for the drug
      repurposing in combination therapy in order to inhibit ALDH activity thus overcoming a
      cisplatin resistance in refractory TGCTs. Indeed, disulfiram in combination with cisplatin
      very efficiently eradicated platinum-resistant NTERA-2 model spheroids and significantly
      inhibited xenograft growth in vivo in our experimental system.

      Based on aforementioned data, investigators suggest that there is strong rationale to inhibit
      ALDH in TGCT. Investigators hypothesize that inactivation of ALDH by disulfiram recover
      cisplatin sensitivity in patients with progressing or relapsing germ cell cancer.

Study Phase

Phase 2

Study Type


Primary Outcome

Overall response rate

Secondary Outcome

 Progression-free survival


Germ Cell Tumor



Study Arms / Comparison Groups

 Treatment arm
Description:  Cisplatin 50mg/m2 day 1 and 2, every 3 weeks, Disulfiram 400mg daily, continuously


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

May 14, 2019

Completion Date

December 31, 2022

Primary Completion Date

December 31, 2021

Eligibility Criteria

        Inclusion Criteria:

          1. Signed written informed consent .

          2. Men aged 18 years or older.

          3. ECOG performance status: 0-1.

          4. Histologically confirmed extracranial primary germ cell cancer, seminoma, or

          5. Rising serum markers (i.e., alpha-fetoprotein and human chorionic gonadotropin) on
             sequential measurement or biopsy-proven unresectable germ cell cancer.

          6. Multiple relapsed/refractory GCTs (at least 2 lines of previous chemotherapy and/or
             patients relapsing after high-dose chemotherapy or for patients non fit enough for
             high-dose chemotherapy.

          7. Primary mediastinal GCTs in first relapse.

          8. Patient's disease must not be amenable to cure with either surgery or chemotherapy in
             the opinion of investigator.

          9. RECIST 1.1 Measurable disease.

         10. Adequate hematologic function defined by ANC > 1500/mm3, platelet count > 100 000/mm3
             and hemoglobin level > 9g/dl.

         11. Adequate liver function defined by a total bilirubin level < 1.5 ULN, and ALT, AST < 3
             ULN or < 5 in case of liver metastases. For subjects with Gilbert's syndrome bilirubin
             > 1.5 × ULN is allowed if no symptoms of compromised liver function are present.

         12. Adequate renal function: measured or calculated (by Cockcroft formula) creatinine
             clearance > 50 ml/min. Cockcroft formula: CLcr = [(140-age) x weight (Kg)]/[72 x creat

         13. At least 4 weeks must have elapsed since the last radiotherapy and/or chemotherapy
             before study entry.

         14. At least 4 weeks must have elapsed since the last major surgery.

         15. Complete recovery from prior surgery, and/or reduction of all adverse events from
             previous systemic therapy or radiotherapy to grade 1.

         16. Absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule.

        Exclusion Criteria:

          1. Patients who do not fit inclusion criteria.

          2. Addiction to alcohol or drugs.

          3. Other prior malignancy except successfully treated nonmelanoma skin cancer .

          4. Need for metronidazole, warfarin and/or theophylline medication, the metabolism of
             which is likely influenced by disulfiram.

          5. Patients who are taking medications metabolized by cytochrome P450 2E1, including
             chlorzoxazone or halothane and its derivatives.

          6. Other concurrent approved or investigational anticancer treatment, including surgery,
             radiotherapy, chemotherapy, biologic-response modifiers, hormone therapy, or

          7. Female patients.

          8. Patients infected by the Human Immunodeficiency Virus (HIV).

          9. Patients with other severe acute or chronic medical condition, or laboratory
             abnormality that would impair, in the judgment of investigator, excess risk associated
             with study treatment, or which, in judgment of the investigator, would make the
             patient inappropriate for entry into this study.

         10. Inability of oral intake, or drug absorbtion (e.g. malabsorption syndrome).

         11. Hypersensitivity to any compound of the drug.

         12. Sexually active men not using highly effective birth control if their partners are
             women of child-bearing potential.




18 Years - N/A

Accepts Healthy Volunteers



Michal Mego, Prof, +421-2-59378352, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

National Cancer Institute, Slovakia

Study Sponsor

Michal Mego, Prof, Principal Investigator, National Cancer Institute, Slovakia

Verification Date

July 2020