MEtronomic TrEatment Option in Advanced bReast cAncer

Breast Cancer Clinical Trial

— METEORA-II  

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 Details — Status: Completed

Administrative data

• NCT number: NCT02954055
• Other study ID #: IBCSG 54-16
• Secondary ID: 2016-002200-39
• Status: Completed
• Phase: Phase 2
• Start date: September 13, 2017
• Est. completion date: November 23, 2022

Study information

• Verified date: February 2024
• Source: ETOP IBCSG Partners Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: November 23, 2022
• Est. primary completion date: November 17, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Paclitaxel
Arm A
• Cyclophosphamide
Arm B
• Capecitabine
Arm B
• Vinorelbine
Arm B

Locations

Country	Name	City	State
Italy	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	Milano
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	Rom
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

Sponsors (1)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Eniu A, Palmieri FM, Perez EA. Weekly administration of docetaxel and paclitaxel in metastatic or advanced breast cancer. Oncologist. 2005 Oct;10(9):665-85. doi: 10.1634/theoncologist.10-9-665. — View Citation

Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. doi: 10.1200/JCO.2008.21.6457. Epub 2010 May 24. — View Citation

Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. doi: 10.1056/NEJMoa072113. — View Citation

Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. doi: 10.1200/JCO.2007.11.6699. — View Citation

Senkus E, Cardoso F, Pagani O. Time for more optimism in metastatic breast cancer? Cancer Treat Rev. 2014 Mar;40(2):220-8. doi: 10.1016/j.ctrv.2013.09.015. Epub 2013 Oct 1. — View Citation

Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009 Feb 19;360(8):790-800. doi: 10.1056/NEJMra0801289. No abstract available. — View Citation

Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. doi: 10.1056/NEJMoa0707056. Erratum In: N Engl J Med. 2008 Jul 3;359(1):106. N Engl J Med. 2009 Apr 16;360(16):1685. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Treatment Failure (TTF) Compared Between Treatment Groups.	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	Frequency of Targeted Adverse Events (Safety and Tolerability).	Frequency of adverse events by type and worst grade experienced.	Time from day 1 of cycle 1 until 28 days after stopping trial treatment.
Secondary	Disease Control	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.
Secondary	Progression Free Survival (PFS)	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.
Secondary	Overall Survival	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.