Trial of Afatinib With Paclitaxel for Neoadjuvant Therapy of TNBC and Research of Biomarkers of Afatinib
Status:
Unknown status
Trial end date:
2017-07-01
Target enrollment:
Participant gender:
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.