DISGCT: Disulfiram and Cisplatin in Refractory TGCTs.

Sponsor
National Cancer Institute, Slovakia (Other)
Overall Status
Recruiting
CT.gov ID
NCT03950830
Collaborator
(none)
20
1
1
43.6
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Study Details

Study Description

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
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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
20 participants
Allocation:
N/A
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).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
Anticipated Primary Completion Date :
Dec 31, 2021
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

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 Names:
  • Antabus
  • Outcome Measures

    Primary Outcome Measures

    1. Overall response rate [24 months]

      Overall response rate by RECIST 1.1

    Secondary Outcome Measures

    1. Progression-free survival [24 months]

      Progression-free survival

    2. Overall survival [24 months]

      Overall survival

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    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.

    1. 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)].

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

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

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

    5. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Cancer Institute Bratislava Slovakia 83310

    Sponsors and Collaborators

    • National Cancer Institute, Slovakia

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute, Slovakia
    ClinicalTrials.gov Identifier:
    NCT03950830
    Other Study ID Numbers:
    • GCT-SK-006
    First Posted:
    May 15, 2019
    Last Update Posted:
    Aug 6, 2020
    Last Verified:
    Jul 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 6, 2020