Clinical Trials /

MEtronomic TrEatment Option in Advanced bReast cAncer

NCT02954055

Description:

This is a multi-center, randomized phase II trial that will randomise women with ER-positive, HER2-negative (Human Epidermal Growth factor Receptor 2-negative) metastatic or locally relapsed breast cancer in a ratio of 1:1 to receive a metronomic regimen of vinorelbine plus cyclophosphamide and capecitabine, or the conventional paclitaxel monotherapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MEtronomic TrEatment Option in Advanced bReast cAncer
  • Official Title: A Randomized Phase II Trial of Metronomic Oral Vinorelbine Plus Cyclophosphamide and Capecitabine (VEX) Versus Weekly Paclitaxel as First-line or Second-line Treatment in Patients With ER-positive/HER2-negative Advanced or Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: IBCSG 54-16
  • SECONDARY ID: 2016-002200-39
  • NCT ID: NCT02954055

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
PaclitaxelPaclitaxel SandozArm A
CyclophosphamideEndoxan BaxterArm B
CapecitabineXelodaArm B
VinorelbineNavelbineArm B

Purpose

This is a multi-center, randomized phase II trial that will randomise women with ER-positive, HER2-negative (Human Epidermal Growth factor Receptor 2-negative) metastatic or locally relapsed breast cancer in a ratio of 1:1 to receive a metronomic regimen of vinorelbine plus cyclophosphamide and capecitabine, or the conventional paclitaxel monotherapy.

Detailed Description

      The prognosis for patients with locally advanced or metastatic disease (ABC) remains poor,
      with a median survival of 2-4 years. About 10% of newly diagnosed BC patients present with
      ABC, and 30% to 50% of patients diagnosed at earlier stages will subsequently develop
      metastatic disease.

      In the first-line treatment of HER2 (Human Epidermal Growth factor Receptor 2) negative ABC
      patients, various chemotherapy regimens can be used including taxanes, which are among the
      most active agents in BC. Single agent response rates range from 20 to 50%. However,
      eventually all patients will progress with a median time to progression of 5 to 7 months. A
      weekly (qw) over a three-weekly (q3w) administration schedule of paclitaxel has been shown to
      be more effective in the metastatic as well as in the adjuvant setting after standard
      chemotherapy

      The VEX regimen was recently investigated within a phase II trial currently ongoing at the
      European Institute of Oncology (IEO) (IEO number IEOS582/111; EudraCT Number: 2010-024266-21;
      title: "A phase II study of metronomic oral chemotherapy with cyclophosphamide plus
      capecitabine and vinorelbine in metastatic breast cancer patients"). Patients received
      vinorelbine 40 mg orally on days 1, 3 and 5 every week, cyclophosphamide 50 mg daily and
      capecitabine 500 mg 3 times a day.

      Given the promising activity of the VEX regimen in a pre-treated population of advanced
      breast cancer patients and the good tolerability, the aim of the present trial is to
      investigate whether the VEX schedule may improve efficacy and tolerability as compared to
      standard paclitaxel treatment in advanced or metastatic ER-positive/HER2-negative breast
      cancer patients.

      The concept of the VEX metronomic treatment is to administer the combination for as long as
      the patient has the possibility of deriving a benefit from it. The time to treatment failure
      (TTF) has been chosen as primary endpoint for this trial. TTF is defined as time from the
      date of randomization to the date when the final dose of trial treatment is administered.
      Chemotherapy may need to be stopped due to lack of tolerability, lack of efficacy or patient
      preference through subjective symptom assessment. TTF is a composite endpoint combining all
      these feasibility aspects of a treatment. It is therefore uniquely suited to the research
      question of the current trial. The secondary endpoints progression-free survival, disease
      control and safety will allow further assessment of the feasibility of the VEX metronomic
      treatment versus the paclitaxel monotherapy regimen.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AActive ComparatorPaclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability.
  • Paclitaxel
Arm BExperimentalMetronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, Capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, Vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability.
  • Cyclophosphamide
  • Capecitabine
  • Vinorelbine

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed HER2‐negative locally advanced or metastatic
             (stage IV) breast cancer.

          -  Maximum of one prior line of chemotherapy for advanced or metastatic breast cancer.

          -  Measurable or non‐measurable, but radiologically evaluable (except for skin lesions),
             disease according to RECIST 1.1 criteria.

          -  Female aged 18 years or older.

          -  Life expectancy > 3 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

          -  ER‐positive disease by local laboratory, determined on most recent available tissue
             (latest biopsy of metastatic lesion, otherwise prior biopsy or surgical specimen).

          -  If previously treated with a taxane in the neoadjuvant or adjuvant setting, the period
             from end of treatment to disease recurrence must have been > 12 months (> 365 days).

          -  Radiation therapy, if given and regardless of site, must be completed at least 2 weeks
             prior to randomization.

          -  Normal hematologic status,

          -  Absolute neutrophil count ≥1000/mm3 (1.0 × 109/L),

          -  Platelets ≥ 100 × 109/L,

          -  Hemoglobin ≥ 9 g/dL (≥ 90 g/L).

          -  Normal renal function: serum creatinine ≤ 1.5 ULN or calculated creatinine clearance ≥
             50 mL/min according to the Cockcroft-Gault formula.

          -  Normal liver function:

          -  Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known
             Gilbert's syndrome, a higher serum total bilirubin (< 3 × ULN) is allowed.

          -  Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3 × ULN; if the patient
             has liver metastases, ALT and AST must be ≤ 5 × ULN.

          -  Women of child bearing potential must have documented negative pregnancy test within 2
             weeks prior to randomization and agree to acceptable birth control (non-hormonal)
             during and up to 6 months after trial therapy.

          -  Written Informed Consent (IC) must be signed and dated by the patient and the
             Investigator prior to starting screening procedures and randomization.

          -  The patient has been informed of and agrees to data transfer and handling, in
             accordance with national data protection guidelines.

        Exclusion Criteria:

          -  More than one prior line of chemotherapy for advanced or metastatic breast cancer

          -  Previous treatment for advanced or metastatic disease with taxanes, or capecitabine or
             vinorelbine or oral cyclophosphamide.

          -  More than 2 lines of previous endocrine therapy for locally advanced or metastatic
             breast cancer.

          -  Known active central nervous system metastases, as indicated by clinical symptoms,
             cerebral edema, and/or progressive growth (patients with history of Central Nervous
             System (CNS) metastases or spinal cord compression are eligible if they are clinically
             and radiologically stable for at least 4 weeks before first dose of trial treatment
             and have not required high-dose steroid treatment in the last 4 weeks).

          -  Peripheral neuropathy grade 2 or higher (CTCAE version 4.0).

          -  Significant uncontrolled cardiac disease (i.e. unstable angina, myocardial infarction
             within prior 6 months), patients classified as having a New York Heart Association
             (NYHA) class III or IV congestive heart failure.

          -  Pregnant or lactating.

          -  Prior history of non‐breast malignancy (except for adequately controlled basal cell
             carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the
             bladder).

          -  Any concurrent condition which in the Investigator's opinion makes it inappropriate
             for the patient to participate in the trial or which would jeopardize compliance with
             the protocol.

          -  Contraindications or known hypersensitivity to the trial medication or excipients.

          -  The use of any anti‐cancer investigational agents within 30 days prior to expected
             start of trial treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Time to treatment failure (TTF) compared between treatment groups.
Time Frame:From date of randomization until the date the final dose of trial treatment was given due to documented progression, lack of tolerability or until further treatment is declined, assessed up to 36 months from enrollment of the first patient.
Safety Issue:
Description:Efficacy and tolerability, measured by time to treatment failure, of metronomic oral vinorelbine plus cyclophosphamide and capecitabine (VEX) versus weekly paclitaxel, using an intent-to-treat analysis approach.

Secondary Outcome Measures

Measure:Frequency of targeted adverse events (safety and tolerability).
Time Frame:Time from day 1 of cycle 1 until 28 days after stopping trial treatment.
Safety Issue:
Description:Frequency of adverse events by type and worst grade experienced.
Measure:Disease control
Time Frame:From date of randomization until the date of first documented progression, assessed up to 36 months from enrollment of the first patient.
Safety Issue:
Description:Best overall response of complete response (CR) or partial response (PR), or stable disease (SD) lasting for at least 24 weeks, measured from randomisation to progression.
Measure:Progression free survival (PFS)
Time Frame:Time from randomization until documented disease progression, assessed up to 36 months from the enrollment of the first patient.
Safety Issue:
Description:Distribution of PFS for each treatment group using Kaplan-Meier; median PFS with two-sided 95% confidence interval (CI). PFS according to RECIST 1.1 criteria or death, whichever occurs first.
Measure:Overall Survival
Time Frame:From day 1 of cycle 1 until death from any cause (censored at date of last assessment of vital status for patients lost to follow up), assessed up to 36 months from the enrollment of the first patient.
Safety Issue:
Description:Overall survival from time of randomisation will be summarised for each treatment group.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:International Breast Cancer Study Group

Trial Keywords

  • locally advanced
  • metastatic
  • breast cancer
  • ER-positive
  • HER2-negative
  • Stage IV

Last Updated

March 17, 2020