Disulfiram and Cisplatin in Refractory TGCTs. (DISGCT)

  • STATUS
    Recruiting
  • days left to enroll
    23
  • participants needed
    20
  • sponsor
    National Cancer Institute, Slovakia
Updated on 8 February 2022
platelet count
renal function
gonadotropin
cancer
measurable disease
major surgery
human chorionic gonadotropin
metastasis
high-dose chemotherapy
cancer chemotherapy
alpha fetoprotein
high dose chemotherapy
germ cell cancer
seminoma
mg++

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).

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.

Details
Condition Germ Cell Tumor
Treatment Disulfiram
Clinical Study IdentifierNCT03950830
SponsorNational Cancer Institute, Slovakia
Last Modified on8 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Signed written informed consent
Men aged 18 years or older
ECOG performance status: 0-1
Histologically confirmed extracranial primary germ cell cancer, seminoma, or nonseminoma
Rising serum markers (i.e., alpha-fetoprotein and human chorionic gonadotropin) on sequential measurement or biopsy-proven unresectable germ cell cancer
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
Primary mediastinal GCTs in first relapse
Patient's disease must not be amenable to cure with either surgery or chemotherapy in the opinion of investigator
RECIST 1.1 Measurable disease
Adequate hematologic function defined by ANC > 1500/mm3, platelet count > 100 000/mm3 and hemoglobin level > 9g/dl
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
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)]
At least 4 weeks must have elapsed since the last radiotherapy and/or chemotherapy before study entry
At least 4 weeks must have elapsed since the last major surgery
Complete recovery from prior surgery, and/or reduction of all adverse events from previous systemic therapy or radiotherapy to grade 1
Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Exclusion Criteria

Patients who do not fit inclusion criteria
Addiction to alcohol or drugs
Other prior malignancy except successfully treated nonmelanoma skin cancer
Need for metronidazole, warfarin and/or theophylline medication, the metabolism of which is likely influenced by disulfiram
Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives
Other concurrent approved or investigational anticancer treatment, including surgery, radiotherapy, chemotherapy, biologic-response modifiers, hormone therapy, or immunotherapy
Female patients
Patients infected by the Human Immunodeficiency Virus (HIV)
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
Inability of oral intake, or drug absorbtion (e.g. malabsorption syndrome)
Hypersensitivity to any compound of the drug
Sexually active men not using highly effective birth control if their partners are women of child-bearing potential
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