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