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
Interventional
Primary Outcome
Overall response rate
Secondary Outcome
Progression-free survival
Condition
Germ Cell Tumor
Intervention
Disulfiram
Study Arms / Comparison Groups
Treatment arm
Description: Cisplatin 50mg/m2 day 1 and 2, every 3 weeks, Disulfiram 400mg daily, continuously
Publications
* 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
Drug
Estimated Enrollment
20
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 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.
Gender
Male
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Michal Mego, Prof, +421-2-59378352, [email protected]
Location Countries
Slovakia
Location Countries
Slovakia
Administrative Informations
NCT ID
NCT03950830
Organization ID
GCT-SK-006
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute, Slovakia
Study Sponsor
Michal Mego, Prof, Principal Investigator, National Cancer Institute, Slovakia
Verification Date
July 2020