Disulfiram and Cisplatin in Refractory TGCTs. (DISGCT)

Phase II Study of Disulfiram and Cisplatin in Refractory TGCTs.

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).

Study Overview

• Status: Completed
• Conditions: Germ Cell Tumor
• Intervention / Treatment: Drug: Disulfiram

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: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Slovakia
  • Bratislava, Slovakia, 83310
    • National Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Overall response rate by RECIST 1.1	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival	24 months
Progression-free survival	Progression-free survival	24 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2019
• Primary Completion (Actual): September 30, 2021
• Study Completion (Actual): January 31, 2022

Study Registration Dates

• First Submitted: May 12, 2019
• First Submitted That Met QC Criteria: May 12, 2019
• First Posted (Actual): May 15, 2019

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Germ Cell and Embryonal; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Disulfiram
• Other Study ID Numbers: GCT-SK-006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No