Trial of Afatinib With Paclitaxel for Neoadjuvant Therapy of TNBC and Research of Biomarkers of Afatinib

Triple Negative Breast Cancer Clinical Trial

Official title: An Open Label, Phase II Trial of Afatinib With Paclitaxel for the Neoadjuvant Treatment of Triple-Negative Breast Cancer and Research of Biomarkers of Activity and Efficacy of Afatinib

Status Recruiting

Clinical Trial Summary

[Background]: Triple-negative breast cancer (TNBC) is defined by a lack of expression of both estrogen and progesterone receptor as well as human epidermal growth factor receptor 2 (HER-2). TNBC is characterized by distinct molecular, histological and unfavorable clinical features despite the high rates of response to chemotherapy. Based on the above reasons, it is important to emergently develop novel therapies and/or treatment strategies to increase treatment efficacies and the survival rate of TNBC.

[Rationale]: Overexpression of epidermal growth factor receptor (EGFR/ErbB1) and EGFR mutation have been reported in TNBC and may therefore be a valid target for anti-tumor therapy in TNBC. Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in triple-negative breast cancer cell lines and xenograft models of breast cancer, and clinical activity in phase I studies. Based on the assumption that uncontrolled ErbB-signaling is directly related to an increased oncogenic potential in TNBC, the studying afatinib in the neoadjuvant treatment of TNBC patients is important and provides a novel therapy.

[Aims] The primary endpoint is to evaluate the pathologic complete response of the combination of afatinib and weekly paclitaxel in TNBC patients receiving neoadjuvant treatment. The secondary endpoints are to evaluate the clinical response and safety of afatinib with and without paclitaxel, and to explore the different afatinib-affecting downstream molecular pathways as well as potential biomarkers predicting the response of afatinib with and without paclitaxel.

[Patients and methods]: Patients with TNBC (clinical T2-T3, N0-N1, M0; clinical T1-3, N1-2, M0; or any T4a tumor) and received neoadjuvant treatment will included in this open, label, multi-center phase II study. Our schema is as follows: (1) Afatinib 40 mg per day for 14 days, then evaluation, every subject will go into the following phase no matter whether she had response or not (2) the following phase (the combination with afatinib and paclitaxel): Afatinib 40 mg per day, day 1 to day 21, in combination with paclitaxel 80 mg/m² on days 1, 8, 15 in a 3-weekly course. In addition to the clinical assessment, we will evaluate the potential predictive biological markers of activity of Afatinib with and without paclitaxel and dynamic changes of molecular makers ([serum and tissue samples: before treatment, 2 weeks after treatment, and operation timing]; potential molecules, such as EGFR, EGFR-signaling, FGFR, FGFR-signaling, ERK, p53, NF-κB, and etc. were evaluated through the immunohistochemical stains, mutation analysis, mRNA [RT-PCR], single nucleotide polymorphism analysis, and FISH analysis). In addition, the genetic expression profiles will be compared between afatinib-responsive and afatinib-unresponsive samples.

[Expected Results]: The promising clinical activity, tolerable toxicity, and potential biomarkers of afatinib with and without paclitaxel in TNBC patients receiving neoadjuvant setting will be demonstrated. The results from this study can be used to conduct a larger trial that would allow us to confirm or validate the hypotheses generated.

Clinical Trial Description

Objects: Phase II study

Primary Objective :

To evaluate the efficacy of combination of afatinib and weekly paclitaxel as assessed by pathologicalresponse in the residual tumor.

Secondary Objectives:

1. Efficacy of afatinib as assessed by the ultrasound of the breast.

2. Adverse effect of afatinib monotherapy and the combination of afatinib and weekly paclitaxel.

3. Correlation between baseline potential biomarkers and radiological response of afatinib monotherapy.

4. Correlation between down- or up-regulation of potential biomarkers (in pre-treatment biopsy and surgical specimen) and radiological response to afatinib and paclitaxel.

5. To identify the pharmacodynamic biomarkers, the following translational researches will be carried out on initial tumor biopsy and surgical specimen.

6. To evaluate the dynamic changes of circulating tumor cells and cell-free DNA after afatinib monotherapy and after the combination of afatinib and weekly paclitaxel. ;

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

• NCT number: NCT02511847
• Study type: Interventional
• Source: National Taiwan University Hospital
• Contact: PeiYing Liu
• Phone: 886-23123456
• Email: tbcc.org@gmail.com
• Status: Recruiting
• Phase: Phase 2
• Start date: August 2015
• Completion date: July 2017