Clinical Trials /

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

NCT04265274

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vinorelbine, Cisplatin, Disulfiram and Copper in CTC_EMT Positive Refractory Metastatic Breast Cancer.
  • Official Title: Phase II Study of Vinorelbine, Cisplatin, Disulfiram and Copper in CTC_EMT Positive Refractory Metastatic Breast Cancer.

Clinical Trial IDs

  • ORG STUDY ID: BREAST-SK-001
  • NCT ID: NCT04265274

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
DisulfiramAntabusDisulfiram, vinorelbin, cisplatin, copper
VinorelbinNavelbineDisulfiram, vinorelbin, cisplatin, copper
CisplatinDisulfiram, vinorelbin, cisplatin, copper
CopperDisulfiram, vinorelbin, cisplatin, copper

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Disulfiram, vinorelbin, cisplatin, copperExperimentalVinorelbine 25mg/m2 day 1 and 8, Cisplatin 75mg/m2 day 1, every 3 weeks, Disulifiram um 400mg daily and 2 mg of elementary Copper daily, continuously.
  • Disulfiram
  • Vinorelbin
  • Cisplatin
  • Copper

Eligibility Criteria

        Inclusion Criteria:1) Female patients with histologically confirmed carcinoma of the
        breast.

        2) CTC_EMT positivity in the peripheral blood. 3) Patients with locally recurrent or
        metastatic disease hormone receptor positive, HER2 negative, who have received at least two
        (and not more than five) prior chemotherapeutic regimens for breast cancer, at least two of
        which were administered for treatment of locally recurrent and/or metastatic disease.

        4) Prior therapy must be documented by the following criteria prior to entry onto study:

          -  Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a
             taxane (e.g., paclitaxel, docetaxel) in any combination or order. Treatment with any
             of these agents is not required if they are contraindicated for a certain patient.

          -  One or two of these regimens may have been administered as adjuvant and/or neoadjuvant
             therapy, but at least 2 must have been given for relapsed or metastatic disease.

          -  Patients must have proved refractory to the most recent chemotherapy, documented by
             progression on or within six (6) months of therapy.

             5) Patients may have additionally been treated with anti-hormonal therapy. 6)
             Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or
             lower, except for stable sensory neuropathy <= Grade 2 and alopecia.

             7) Age >= 18 years. 8) Eastern Cooperative Oncology Group (ECOG) Performance Status of
             0 to 2. 9) Life expectancy of >= 3 months. 10) Adequate renal function as evidenced by
             calculated creatinine clearance >= 40 mL/min per the Cockcroft and Gault formula.

             11) Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) >=
             1.5 x 10^9/L, hemoglobin >= 9.0 g/dL (a hemoglobin <10.0 g/dL is acceptable if it is
             corrected by growth factor or transfusion), and platelet count >= 100 x 10^9/L.

             12) Adequate liver function as evidenced by bilirubin <= 1.5 times the upper limits of
             normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
             aminotransferase (AST) <= 3 x ULN (in the case of liver metastases <= 5 x ULN), unless
             there are bone metastases, in which case liver specific alkaline phosphatase must be
             separated from the total and used to assess the liver function instead of the total
             alkaline phosphatase. In case alkaline phosphatase is >3 x ULN (in absence of liver
             metastases) or > 5 x ULN (in presence of liver metastases) AND patient is known to
             have bone metastases, the liver specific alkaline phosphatase must be separated from
             the total and used to assess the liver function instead of the total alkaline
             phosphatase.

             13) Patients willing and able to comply with the study protocol for the duration of
             the study.

             14) Written informed consent prior to any study-specific screening procedures with
             theunderstanding that the patient may withdraw consent at any time without prejudice.

        Exclusion Criteria:

          1. Patients who have received any of the following treatments within the specified period
             before study treatment start: chemotherapy, radiation, trastuzumab or hormonal therapy
             within three weeks, any investigational drug within four weeks, radiation therapy
             encompassing > 30% of marrow.

          2. Addiction to alcohol or drugs.

          3. Need for metronidazole, warfarin and/or theophylline medication, the metabolism of
             which is likely influenced by disulfiram and copper, see Table 4.

          4. Patients who are taking medications metabolized by cytochrome P450 2E1, including
             chlorzoxazone or halothane and its derivatives, see Table 4.

          5. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring
             active treatment, including the use of oxygen.

          6. Patients with brain or subdural metastases are not eligible, unless they have
             completed local therapy and have discontinued the use of corticosteroids for this
             indication for at least 4 weeks before starting treatment in this study. Any signs
             (e.g., radiologic) and/or symptoms of brain metastases must be stable for at least 4
             weeks before starting study treatment; radiographic stability should be determined by
             comparing a contrast-enhanced computed tomography or magnetic resonance imaging brain
             scan performed during screening to a prior scan performed at least 4 weeks earlier.

          7. Patients with meningeal carcinomatosis.

          8. Women who are pregnant or breast-feeding; women of childbearing potential with either
             a positive pregnancy test at screening or no pregnancy test; women of childbearing
             potential unless (1) surgically sterile or (2) using adequate measures of
             contraception in the opinion of the Investigator. Perimenopausal women must be
             amenorrheic for at least 12 months to be considered of non-childbearing potential.

          9. Severe/uncontrolled intercurrent illness/infection.

         10. Patients with organ allografts requiring immunosuppression.

         11. Patients with known positive HIV status.

         12. Hemochromatosis.

         13. Patients who have had a prior malignancy, other than previous breast cancer, carcinoma
             in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was
             diagnosed and definitively treated >= 5 years previously with no subsequent evidence
             of recurrence.

         14. Patients with pre-existing neuropathy > Grade 2.

         15. Patients with other significant disease or disorders that, in the Investigator's
             opinion, would exclude the patient from the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rates
Time Frame:6 months
Safety Issue:
Description:Response rate according to RECIST

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:12 months
Safety Issue:
Description:Time from first administration of the study drug till progression
Measure:overall survival
Time Frame:12 months
Safety Issue:
Description:Time from first administration of the study drug till death

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute, Slovakia

Trial Keywords

  • metastatic breast cancer, vinorelbin, cisplatin, disulfiram

Last Updated

February 9, 2020