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Trial record 2 of 1643 for:    Slovakia

Disulfiram and Cisplatin in Refractory TGCTs. (DISGCT)

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ClinicalTrials.gov Identifier: NCT03950830
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : May 24, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute, Slovakia

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).

Condition or disease Intervention/treatment Phase
Germ Cell Tumor Drug: Disulfiram Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Non-randomized, open-label, single center trial to assess efficacy (as measured by overall response rate of disulfiram and cisplatin in patients with multiple relapsed/refractory germ cell tumors (GCTs).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Disulfiram and Cisplatin in Refractory TGCTs.
Actual Study Start Date : May 14, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment arm
Cisplatin 50mg/m2 day 1 and 2, every 3 weeks, Disulfiram 400mg daily, continuously
Drug: Disulfiram
Disulfiram 400mg daily, continuously
Other Name: Antabus




Primary Outcome Measures :
  1. Overall response rate [ Time Frame: 24 months ]
    Overall response rate by RECIST 1.1


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 24 months ]
    Progression-free survival

  2. Overall survival [ Time Frame: 24 months ]
    Overall survival



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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 nonseminoma.
  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 (mg/dl)].
  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 immunotherapy.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03950830


Contacts
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Contact: Michal Mego, Prof +421-2-59378352 michal.mego@nou.sk
Contact: Daniela Svetlovska, Dr +421-2-59378592 daniela.svetlovska@nou.sk

Locations
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Slovakia
National Cancer Institute Recruiting
Bratislava, Slovakia, 83310
Contact: Michal Mego, Assoc. Prof    +421259378 ext 366    michal.mego@nou.sk   
Contact: Jozef Mardiak, Prof    +421259378 ext 108    jozef.mardiak@nou.sk   
Principal Investigator: Jozef Mardiak, Prof         
Principal Investigator: Michal Mego, Assoc. Prof         
Sponsors and Collaborators
National Cancer Institute, Slovakia
Investigators
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Principal Investigator: Michal Mego, Prof National Cancer Institute, Slovakia

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Responsible Party: National Cancer Institute, Slovakia
ClinicalTrials.gov Identifier: NCT03950830     History of Changes
Other Study ID Numbers: GCT-SK-006
First Posted: May 15, 2019    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Cisplatin
Disulfiram
Antineoplastic Agents
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action