NCT04265274

Vinorelbine, Cisplatin, Disulfiram and Copper in CTC_EMT Positive Refractory Metastatic Breast Cancer.

Phase II Study of Vinorelbine, Cisplatin, Disulfiram and Copper in CTC_EMT Positive Refractory Metastatic Breast Cancer.

• Status: Withdrawn
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: National Cancer Institute, Slovakia · Other Government
• Sex: Female
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a proof-of-concept study to define efficacy of vinorelbine, cisplatin, disulfiram and copper in CTC\_EMT positive refractory metastatic hormone receptor positive, HER2 negative breast cancer.

Detailed description

Despite advances in breast cancer prevention, diagnosis, and therapy, 5-10% of patients with breast cancer have metastatic disease at initial presentation, and approximately 30% of patients with breast cancer develop metastatic disease during the course of disease. Metastatic cascade is a multistep process that enables the migration of tumor cells from the primary site to a distant location, where they can potentially establish a new cancer growth. To execute the metastatic cascade, epithelial cancer cells must detach from the primary tumor, pass through the peripheral circulation, extravasate at the distant site and create a new tumor. Experimental and clinical data suggest a close relationship between activation of EMT program and generation of CTCs. EMT is associated with a set of molecular changes in epithelial cancer cells that results in increased motility and the induction of proteases that are involved in degradation of the extracellular matrix facilitating thus invasion and intravasation into the bloodstream. EMT has also been linked to the stem cell phenotype and resistance to apoptotic signals, facilitating EMT-derived CTCs to survive in foreign environments. Cancer stem cell phenotype is closely related to ALDH expression. Several studies showed that CTCs with EMT phenotype is associated with inferior outcome in primary as well as in metastatic setting. In a biomarker study in primary breast cancer, CTC\_EMT were detected in 77 (18.0%) of patients. Patients without detectable CTC\_EMT in the peripheral blood had significantly superior DFS compared to patients with detectable CTC\_EMT (HR = 0.42, 95%CI 0.22 - 0.78, p = 0.0003). Prognostic value of CTC\_EMT was demonstrated in all subgroups of patients, most pronounced in hormone receptor positive, HER2 negative subgroup. In multivariate analysis, presence of CTC\_EMT, axillary nodal involvement and hormone receptor status were independently associated with DFS. Presence of CTC\_EMT could lead to better identification of patients with increased risk of recurrence, especially in hormone receptor positive, HER-2 negative primary breast cancer patients. Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Based on aforementioned data, it is suggested that there is strong rationale to inhibit ALDH in MBC. Inactivation of ALDH by disulfiram/copper will be lead to increase of objective response rate in patients with refractory MBC.

Conditions

• Metastatic Breast Cancer

Interventions

Type	Name	Description
DRUG	Disulfiram	dosing 400mg daily
DRUG	Vinorelbin	25mg/m2 day 1 and 8,
DRUG	Cisplatin	75mg/m2 day 1
DRUG	Copper	2 mg of elementary Copper daily

Timeline

• Start date: 2020-01-01
• Primary completion: 2022-01-01
• Completion: 2023-01-01
• First posted: 2020-02-11
• Last updated: 2023-10-06

Locations

1 site across 1 country: Slovakia