MEtronomic TrEatment Option in Advanced bReast cAncer

NCT ID: NCT02954055

Last Updated: 2024-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-13
• Study Completion Date: 2022-11-23

Brief Summary

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A

Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability.

Group Type: ACTIVE_COMPARATOR

Paclitaxel

Intervention Type: DRUG

Arm A

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.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Arm B

Capecitabine

Intervention Type: DRUG

Arm B

Vinorelbine

Intervention Type: DRUG

Arm B

Interventions

Paclitaxel

Arm A

Intervention Type: DRUG

Cyclophosphamide

Arm B

Intervention Type: DRUG

Capecitabine

Arm B

Intervention Type: DRUG

Vinorelbine

Arm B

Intervention Type: DRUG

Other Intervention Names

Paclitaxel Sandoz; Endoxan Baxter; Xeloda; Navelbine

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elisabetta Munzone, MD

Role: STUDY_CHAIR

European Institute of Oncology

Locations

Centro di Riferimento Oncologico (CRO)

Aviano, , Italy

A.O.U. di Bologna Policlinico S. Orsola-Malpighi Viale Ercolani 4/2

Bologna, , Italy

Ospedale di Bolzano Oncologia Medica Via lorenz Bohler 5

Bolzano, , Italy

Aziendale Spedali Civili di Brescia SSVD Breast Unit P.le Spedali Civili 1

Brescia, , Italy

"Antonio Perrino" Division of Medical Oncology Strada Statale 7 APPIA

Brindisi, , Italy

Candiolo Cancer Institute (FPO-IRCCS)

Candiolo, , Italy

ASST Di Cremona, Unità di Patologia Mammaria-Breast Unit VIALE CONCORDIA 1

Cremona, , Italy

Ospedale Misericordia di Grosseto

Grosseto, , Italy

ASST Ovest Milanese Oncology Department Via Papa Giovanni Paolo II

Legnano, , Italy

Ospedale Generale Provinciale di Macerata

Macerata, , Italy

IRST IRCCS Division of medical oncology Via Maroncelli 40

Meldola, , Italy

Istituto Europeo di Oncologia, Division of Medical Senology, Via Ripamonti 435

Milan, , Italy

Osp. Sacro Cuore Don Calabria Division in Medical Oncology

Negrar, , Italy

Istituti Clinici Scientifici Maugeri SpA SB

Pavia, , Italy

Ospedale S. Maria delle Croci

Ravenna, , Italy

Ospedale Infermi Uo Oncologia Via Settembrini 2

Rimini, , Italy

Fondazione Policlinico Universitario A.Gemelli

Rome, , Italy

A.O.U Città della Salute e della Scienza di Torino SSCVD Oncologia Medica Senologica (Oncology Dep.- Breast Unit) Via Cherasco 23

Torino, , Italy

Asst Bg Ovest Ospedale Di Treviglio

Treviglio, , Italy

ASST Settelaghi - Ospedale di Circolo e Fondazione Macchi U.O Oncologia Medica Viale L. Borri, 57

Varese, , Italy

Countries

Italy

References

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Munzone E, Regan MM, Cinieri S, Montagna E, Orlando L, Shi R, Campadelli E, Gianni L, Palleschi M, Petrelli F, Bengala C, Generali D, Collova E, Puglisi F, Cretella E, Zamagni C, Chini C, Ruepp B, Loi S, Colleoni M; International Breast Cancer Study Group (IBCSG). Efficacy of Metronomic Oral Vinorelbine, Cyclophosphamide, and Capecitabine vs Weekly Intravenous Paclitaxel in Patients With Estrogen Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: Final Results From the Phase 2 METEORA-II Randomized Clinical Trial. JAMA Oncol. 2023 Sep 1;9(9):1267-1272. doi: 10.1001/jamaoncol.2023.2150.

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2016-002200-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

IBCSG 54-16

Identifier Type: -

Identifier Source: org_study_id