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出境医 / 临床实验 / Disulfiram and Cisplatin in Refractory TGCTs. (DISGCT)

Disulfiram and Cisplatin in Refractory TGCTs. (DISGCT)

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
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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated 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).
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
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 Name: Antabus

Outcome Measures
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


Eligibility Criteria
Layout table for eligibility information
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.
Contacts and Locations

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

Locations
Layout table for location information
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
Layout table for investigator information
Principal Investigator: Michal Mego, Prof National Cancer Institute, Slovakia
Tracking Information
First Submitted Date  ICMJE May 12, 2019
First Posted Date  ICMJE May 15, 2019
Last Update Posted Date August 6, 2020
Actual Study Start Date  ICMJE May 14, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 12, 2019)
Overall response rate [ Time Frame: 24 months ]
Overall response rate by RECIST 1.1
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2019)
  • Progression-free survival [ Time Frame: 24 months ]
    Progression-free survival
  • Overall survival [ Time Frame: 24 months ]
    Overall survival
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Disulfiram and Cisplatin in Refractory TGCTs.
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Germ Cell Tumor
Intervention  ICMJE Drug: Disulfiram
Disulfiram 400mg daily, continuously
Other Name: Antabus
Study Arms  ICMJE Experimental: Treatment arm
Cisplatin 50mg/m2 day 1 and 2, every 3 weeks, Disulfiram 400mg daily, continuously
Intervention: Drug: Disulfiram
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 12, 2019)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michal Mego, Prof +421-2-59378352 michal.mego@nou.sk
Contact: Daniela Svetlovska, Dr +421-2-59378592 daniela.svetlovska@nou.sk
Listed Location Countries  ICMJE Slovakia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03950830
Other Study ID Numbers  ICMJE GCT-SK-006
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party National Cancer Institute, Slovakia
Study Sponsor  ICMJE National Cancer Institute, Slovakia
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Michal Mego, Prof National Cancer Institute, Slovakia
PRS Account National Cancer Institute, Slovakia
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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