MEtronomic TrEatment Option in Advanced bReast cAncer (METEORA-II)

February 12, 2024 updated by: ETOP IBCSG Partners Foundation

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

140

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Aviano, Italy
        • Centro di Riferimento Oncologico (CRO)
      • Bologna, Italy, 40138
        • A.O.U. di Bologna Policlinico S. Orsola-Malpighi Viale Ercolani 4/2
      • Bolzano, Italy, 39100
        • Ospedale di Bolzano Oncologia Medica Via lorenz Bohler 5
      • Brescia, Italy, 25123
        • Aziendale Spedali Civili di Brescia SSVD Breast Unit P.le Spedali Civili 1
      • Brindisi, Italy, 72100
        • "Antonio Perrino" Division of Medical Oncology Strada Statale 7 APPIA
      • Candiolo, Italy
        • Candiolo Cancer Institute (FPO-IRCCS)
      • Cremona, Italy, 26100
        • ASST Di Cremona, Unità di Patologia Mammaria-Breast Unit VIALE CONCORDIA 1
      • Grosseto, Italy
        • Ospedale Misericordia di Grosseto
      • Legnano, Italy
        • ASST Ovest Milanese Oncology Department Via Papa Giovanni Paolo II
      • Macerata, Italy
        • Ospedale Generale Provinciale di Macerata
      • Meldola, Italy, 47014
        • IRST IRCCS Division of medical oncology Via Maroncelli 40
      • Milano, Italy, 20141
        • Istituto Europeo di Oncologia, Division of Medical Senology, Via Ripamonti 435
      • Negrar, Italy
        • Osp. Sacro Cuore Don Calabria Division in Medical Oncology
      • Pavia, Italy
        • Istituti Clinici Scientifici Maugeri Spa SB
      • Ravenna, Italy
        • Ospedale S. Maria Delle Croci
      • Rimini, Italy, 47923
        • Ospedale Infermi Uo Oncologia Via Settembrini 2
      • Rom, Italy
        • Fondazione Policlinico Universitario A.Gemelli
      • Torino, Italy, 10126
        • A.O.U Città della Salute e della Scienza di Torino SSCVD Oncologia Medica Senologica (Oncology Dep.- Breast Unit) Via Cherasco 23
      • Treviglio, Italy
        • ASST BG OVEST Ospedale di Treviglio
      • Varese, Italy, 21100
        • ASST Settelaghi - Ospedale di Circolo e Fondazione Macchi U.O Oncologia Medica Viale L. Borri, 57

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm A
Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability.
Drug: Paclitaxel
Arm A
Other Names:
  • Paclitaxel Sandoz
Experimental: Arm B

Metronomic 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.
Drug: Cyclophosphamide
Arm B
Other Names:
  • Endoxan Baxter
Drug: Capecitabine
Arm B
Other Names:
  • Xeloda
Drug: Vinorelbine
Arm B
Other Names:
  • Navelbine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to Treatment Failure (TTF) Compared Between Treatment Groups.
Time Frame: Assessed at the start of every 4-week (28-day) treatment cycle from randomization to the end of treatment date or discontinuation; median follow-up was 29 months, with a minimum of 0.2 months and maximum of 48.5 months.
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.
Assessed at the start of every 4-week (28-day) treatment cycle from randomization to the end of treatment date or discontinuation; median follow-up was 29 months, with a minimum of 0.2 months and maximum of 48.5 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Overall survival from time of randomisation will be summarised for each treatment group.
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.
Frequency of Targeted Adverse Events (Safety and Tolerability).
Time Frame: Time from day 1 of cycle 1 until 28 days after stopping trial treatment.
Frequency of adverse events by type and worst grade experienced.
Time from day 1 of cycle 1 until 28 days after stopping trial treatment.
Disease Control
Time Frame: Tumor measurements were assessed at baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression on the basis of clinical and radiological tumor assessments, on average approximately 9 months.
Defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) (or non-CR/non-PD in the case of non-measurable disease only) lasting for at least 24 weeks (at least 2 scans), measured from randomization until first documentation of progressive disease. Best overall response was defined as best response recorded from randomization across all time points until disease progression. Confirmation of partial or complete response by an additional scan was not requested in this trial. Disease response and progression were assessed according to the revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
Tumor measurements were assessed at baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression on the basis of clinical and radiological tumor assessments, on average approximately 9 months.
Progression Free Survival (PFS)
Time Frame: Tumor measurements were assessed at baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression on the basis of clinical and radiological tumor assessments, on average approximately 9 months.
PFS was defined as time from randomization until documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria or death, whichever occurred first; the death must have occurred within an interval of time corresponding to the interval of tumor re-evaluations. For patients without progression, follow-up was censored at the date of last disease assessment.
Tumor measurements were assessed at baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression on the basis of clinical and radiological tumor assessments, on average approximately 9 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ETOP IBCSG Partners Foundation

Investigators

  • Study Chair: Elisabetta Munzone, MD, European Institute of Oncology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 13, 2017

Primary Completion (Actual)

November 17, 2021

Study Completion (Actual)

November 23, 2022

Study Registration Dates

First Submitted

September 26, 2016

First Submitted That Met QC Criteria

November 1, 2016

First Posted (Estimated)

November 3, 2016

Study Record Updates

Last Update Posted (Estimated)

February 26, 2024

Last Update Submitted That Met QC Criteria

February 12, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IBCSG 54-16
  • 2016-002200-39 (EudraCT Number)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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