CONCEPT: Capecitabine in Combination With Aromatase Inhibitor Versus Aromatase Inhibitors, in Hormonal Receptor Positive Recurrent or Metastatic Breast Cancer Patients, Randomized Controlled Study

Sponsor

Ain Shams University (Other)

Overall Status

Unknown status

CT.gov ID

NCT04012918

Collaborator

(none)

124

Enrollment

Location

Arms

29.1

Anticipated Duration (Months)

4.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Women with recurrent or metastatic breast cancer who are hormone receptor positive are candidates for first line hormonal therapy including aromatase inhibitors. In the past few years new combination therapies became available as fulvastrant or palbociclib with letrezole; increasing the progression free survival (PFS). A retrospective study showed that combination of capecitabine with aromatase inhibitors increase PFS as 1st and 2nd line line treatment another prospective study showed the same results. The aim of our study is confirm such data by a randomized controlled trial.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Capecitabine plus aromatase inhibitor Drug: A.I.	Phase 2

Detailed Description

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide, accounting for 25% of total cancer cases (Globocan, 2012) It ranks as the most prevalent cancer among women in the Middle East and Northern Africa (Ferlay et al., 2015). In Egypt, breast cancer is the most common type of cancer among females (Ibrahim et al., 2014).

Survival of breast cancer patients depends on the disease stage. Most of the patients with localized disease experience long-term disease-free survival. Meanwhile, those who develop metastasis have a 5-year relative survival of only 24% (Siegel et al, 2015). Hormonal receptor positive (HR +ve) represent the most common subset (almost 70%) in both early and advanced disease (Clarke et al., 2012).

It is crucial to determine the menopausal status before initiation of treatment. For HR +ve / Her 2-negative metastatic breast cancer patients who premenopausal; If the patient had Disease free survival (DFS) of 12 months or more, or if she was diagnosed with metastasis de novo, the recommended first line is either ovarian ablation plus tamoxifen or aromatase inhibitor (Cardoso et al., 2017). For postmenopausal patients aromatase inhibitors are recommended with median progression-free survival (PFS) between 8 and 10 months (Bonneterre et al., 2000) and 10 months (Paridaens et al., 2008).

Chemotherapy regimens that are prescribed in hormone receptor-positive patients includes microtubule inhibitors (including taxanes and vinca alkaloids), anthracyclines, gemcitabine, cyclophosphamide and capecitabine. But endocrinal therapy is preferred as long as the patient is not in visceral crisis (Cardoso et al., 2017).

Recently new drugs that increased progression free survival (PFS) has been approved in the treatment of HR +ve metastatic breast cancer (MBC) as fulvastrant (Selective estrogen receptor modulator) (Ellis et al., 2015) and palbocilib (Ck4/6 inhibitor) (Finn et al., 2015) as first line and eveirolimus (mTor inhibitor)(Pritchard et al., 2012) as second line.

The optimum sequence of endocrinal treatment and chemotherapy has not been fully clarified, It is of great importance to bear in mind that the goal of treatment in recurrent and metastatic breast cancer is extending the progression free survival (PFS) and sustaining a good quality of life (Cardoso et al., 2017).

A retrospective study by Shankar et al. that compared between combination of capecitabine and aromatase inhibitor (AI) versus capecitabine alone versus aromatase inhibitor alone showed that the median PFS of first-line treatment was significantly better for the combination with PFS 21 months vs 8.0 months for capecitabine and 15.0 months for AI. For second-line treatment, the PFS was longer in the combination compared with capecitabine and Al groups (18 months vs. 5.0 months vs. 11.0 months, respectively) (Shankar et al., 2015).

Alvarado et al, compared combination aromatase inhibitor plus capecitabine versus capecitabine alone versus aromatase inhibitor alone. The median PFS of first-line treatment was significantly better for the combination (PFS not-reached for combination vs.3.0 m for capecitabine and 13.0 m for AI, p<0.0001). For second-line treatment, the PFS was longer in the combination compared to capecitabine and AI (PFS not reached vs. 6.0 m vs.13.0 m, respectively, p=0-041) (Alvarado et al., 2012).

In China a Phase II trial assessed the use of of metronomic oral capecitabine therapy combined with aromatase inhibitors in postmenopausal metastatic and recurrent breast cancer resistant to first-line aromataseinhibitors and the results showed overall Response Rate (ORR) 70.5% and median PFS 9.57 months (L. Jian-wei et al., 2015). Lee S. Schwartzberg conducted a phase II trial which results showed that fulvastrant with metronomic capecitabine for women with HR-Positive, HER2-Negative MBC has Median PFS was 14.98 months (Schwartzberg et al., 2014).

Capecitabine; being cheaper and more available in economically disadvantaged countries together with the promising results of the previous retrospective trial by Shankar et al and the prospective trial by Alvarado Miranda et al ; further confirmation of such results by a prospective randomized clinical trial is crucial. Currently a phase III trial under the title of "Metronomic Capecitabine Plus Aromatase Inhibitor for First Line Treatment in HR(+), Her2(-) Metastatic Breast Cancer" with the primary results expected to be published on 2021 (Sun Yat-sen University, 2016).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

124 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Capecitabine in Combination With Aromatase Inhibitor Versus Aromatase Inhibitors, in Hormonal Receptor Positive Recurrent or Metastatic Breast Cancer Patients, Randomized Controlled Study (CONCEPT Trial)

Actual Study Start Date :

Aug 30, 2018

Anticipated Primary Completion Date :

Aug 1, 2020

Anticipated Study Completion Date :

Feb 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A.I. + Capeciabine Patients will receive Capecitabine 625 mg/m2 bid PO for 14 days to be repeated every 21 days until progression in combination with aromatase inhibitor if postmenopausal, addition of LHRH agonist will be added if premenopausal.	Drug: Capecitabine plus aromatase inhibitor Capecitabine 625 mg/m2 bid PO for 14 days to be repeated every 21 days until progression in combination with aromatase inhibitor if postmenopausal, addition of LHRH agonist will be added if premenopausal.
Active Comparator: A.I Patients will receive aromatase inhibitors ( letrozole 2.5 mg PO per day or Anastrozole 1 mg PO per day or aromasin 25 mg PO per day) if post-menopausal, if premenopausal leutnising hormone releasing hormone (LHRH) agonist will be added to the aromatase inhibitor.	Drug: A.I. aromatase inhibitors ( letrozole 2.5 mg PO per day or Anastrozole 1 mg PO per day or aromasin 25 mg PO per day) if post-menopausal, if premenopausal leutnising hormone releasing hormone (LHRH) agonist will be added to the aromatase inhibitor

Arm

Intervention/Treatment

Experimental: A.I. + Capeciabine

Patients will receive Capecitabine 625 mg/m2 bid PO for 14 days to be repeated every 21 days until progression in combination with aromatase inhibitor if postmenopausal, addition of LHRH agonist will be added if premenopausal.

Drug: Capecitabine plus aromatase inhibitor

Capecitabine 625 mg/m2 bid PO for 14 days to be repeated every 21 days until progression in combination with aromatase inhibitor if postmenopausal, addition of LHRH agonist will be added if premenopausal.

Active Comparator: A.I

Patients will receive aromatase inhibitors ( letrozole 2.5 mg PO per day or Anastrozole 1 mg PO per day or aromasin 25 mg PO per day) if post-menopausal, if premenopausal leutnising hormone releasing hormone (LHRH) agonist will be added to the aromatase inhibitor.

Drug: A.I.

aromatase inhibitors ( letrozole 2.5 mg PO per day or Anastrozole 1 mg PO per day or aromasin 25 mg PO per day) if post-menopausal, if premenopausal leutnising hormone releasing hormone (LHRH) agonist will be added to the aromatase inhibitor

Outcome Measures

Primary Outcome Measures

Progress-free survival [up to 24 months]
Time from randomization to the first documentation of objective tumor progression or to death due to any cause or Intolerable toxicity.

Secondary Outcome Measures

Adverse events [till progression or up to 24 months whichever earlier]
Detailed Description and grading of adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult women with locoregionally recurrent or metastatic disease not amenable to curative therapy
Eastern Cooperative Oncology Group (ECOG) 0-2
Hormone receptor positive
No prior systemic anti-cancer therapy for advanced ER+ disease ( hormonal therapy)
Measurable disease defined by revised RECIST criteria (version 1.1), or bone-only disease
normal laboratory values
Postmenopausal or premenopausal with oophorectomy (medical or surgical).

Exclusion Criteria:

Patients with advanced, symptomatic, visceral spread that are at risk of life threatening complication in the short term
Prior (neo) adjuvant treatment with same aromatase inhibitor type with DFI =< 12 months from completion of treatment.
Known uncontrolled or symptomatic central nervous system metastases
Second primary malignancy
Serious uncontrolled intercurrent infections or intercurrent medical or psychiatric illness
unable to swallow tablets, or malabsorption patients.
unwilling or unable to comply with study protocol or unable to meet the follow up.
patients who researchers considered were not suitable to participate.