Conditions: Breast Cancer
Keywords: Apatinib HER-2 Negative Chest wall Metastasis Multicenter Phase II Study Breast cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
The treatment of the patients with recurrent and metastatic breast cancer remains a major problem. There is still a lack of effective targeted therapy for Her-2 negative breast cancer.Based on the present researches on the anti-angiogenesis drugs in advanced breast cancer, the investigators believe that it is necessary to further explore the efficacy and safety of apatinib in advanced breast cancer.

Detailed description:
With the comprehensive treatment of breast cancer wildly used in the clinical practice, the life quality of the patients with breast cancer has been improved greatly, and the survival of the patients has been extended as well. However, the treatment of the patients with recurrent and metastatic breast cancer remains a major problem. There is still a lack of effective targeted therapy for Her-2 negative breast cancer.

Based on the present researches on the anti-angiogenesis drugs in advanced breast cancer, the investigators believe that it is necessary to further explore the efficacy and safety of apatinib in advanced breast cancer. The aim of this research is to evaluate the progression-free survival (PFS) of the patients with HER-2 negative advanced breast cancer with chest wall metastasis in the treatment of apatinib.

Arms:
arm 1: Patients With HER-2 Negative Advanced Breast Cancer With Chest Wall Metastasis; Dosing regimen: apatinib tablets: 500 mg, Po, QD; 4 weeks as a cycle, continuous treatment until disease progression, death or intolerable toxicity (giving endocrine therapy simultaneously if hormone receptor positive)

Interventions: intervention 1: Apatinib
Intervention descriptions: intervention 1: Dosing regimen: apatinib tablets: 500 mg, Po, QD; 4 weeks as a cycle, continuous treatment until disease progression, death or intolerable toxicity (giving endocrine therapy simultaneously if hormone receptor positive)

Protocol document:
Prot_SAP_000.pdf: 
Apatinib in the treatment of HER-2 negative advanced breast cancer 
with chest wall metastasis：Multicenter Phase II clinical trial 
 
Protocol ID: 2016YJZ19 
ClinicalTrials.gov ID: NCT02878057 
 
 
Doctument date: September, 2020 
 
 


Introduction 
Tumor metastasis is responsible for most of cancer deaths. Once diagnosed of breast 
cancer (BC), 25-50% of patients will eventually have metastasis in subsequent years. The 
mechanism of metastasis is a complex, multistep biological process, involving a multitude of genes, 
angiogenesis and biomolecules. Different molecular subtypes tend to have different initial 
metastatic sites. For instance, BC with HER2-positive to liver, triple-negative to lung and 
hormonal receptor positive (HR+) to bone were most common. However, despite of subtype, 
the rate of chest wall and lymph node metastasis is higher in all molecular subgroups. Recently, 
Song et al found that neutrophil extracellular traps (NETs) are abundant in the liver metastases of 
patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver 
metastases in patients with early-stage BC. This indicates that studying organ specificity of tumor 
metastasis may also allow us to understand tumor behavior and lead to improvement of our 
therapeutic approach.  
Angiogenesis serves an important role in tumor growth, invasion and metastasis in BC, while 
vascular endothelial growth factor (VEGF) and its receptors, specifically VEGF receptor 2 (VEGFR2), 
are predominantly responsible for angiogenic signaling. Bevacizumab (BEV) is a monoclonal antibody 
that binds to VEGF and inhibits the development of tumor vasculature, which has been proven to 
significantly increase progression free survival (PFS) when added to first line chemotherapy in MBC. 
VEGF-tyrosine kinases inhibitors (VEGF-TKIs) such as sunitinib and sorafenib have shown potential 
anti-tumor efficacy in MBC when combined with chemotherapies.  
Apatinib is also an oral TKI that selectively inhibits VEGFR-2, inhibiting tumor angiogenesis, 
and has reported activity in BC. However, as BC with a chest wall metastasis (CWM) has rich vascular 
distribution, whether apatinib is also effective for BC with a CWM remains unknown. Precision 
treatment usually refers to treatment based on molecular markers. Therefore, in current clinical 
trial designs, organ specificity or organs are usually not the main consideration. Nevertheless, 
in our clinical practice, we found that type of organ metastasis was difference among molecular 
subtype. Patients with CWM may have more VEGFR expression, and rich neovascularization, 
which could have a better response to angiogenesis inhibitors. We found that the using of BEV 
or apatinib can rapidly shrink the mass in the chest wall, especially when the tumor is filled 
with rich blood vessels. Therefore, we designed this clinical trial, based on the characteristics 
of organs. To the best of our knowledge, this is the first study to assess the efficacy and safety of 
apatinib in HER-2 negative advanced breast cancer (ABC) with a CWM based on organ specificity. 
 


Material and Methods 
Patients and eligibility criteria 
Inclusion criteria included women (≥18 years of age) with HER-2 negative ABC with CWM 
confirmed by histology or cytological examination, underwent first line chemotherapy regimen or 
cannot tolerate standard first-line treatment, having Eastern Cooperative Oncology Group 
performance status (ECOG PS) of 0 or 1, having at least one measurable site of disease according to 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria that has not been previously 
irradiated. All patients had adequate hematologic, coagulation, hepatic, renal, and cardiac function, 
and had provided written, informed consent. 
Patients were excluded for the following additional reasons: radiotherapy within 28 days before 
enrollment (radiotherapy to relieve metastatic bone pain before enrollment is permitted, but the 
irradiated medullary bone shall not exceed 30% of the total amount); symptomatic metastatic 
carcinoma to central nervous system; other carcinomas within 5 years; uncontrolled hypertension 
with antihypertensive therapy; ischemia of the myocardium (≥grade 2) or myocardial infarction, 
arrhythmia (≥grade 2, QTcF> 470 ms); grade III-IV cardiac insufficiency according to NYHA 
standard, or left ventricular ejection fraction (LVEF)＜50%; gastrointestinal disorder or other 
factors(dysphagia, chronic diarrhea or intestinal obstruction) that could interfere with drug 
absorption. 
The study was conducted in accordance with the World Medical Association Declaration of 
Helsinki, guidelines of the International Conference for Harmonisation/ Good Clinical Practice. This 
study was approved by the Ethics Committee of Beijing Cancer Hospital. Written informed consent 
was provided from all patients (2016YJZ19-GZ01). This trial was registered with ClinicalTrials.gov 
(NCT02878057). 
 
Drug administration 
Initially, all patients received apatinib 500 mg/d as the starting dose, and once a day (qd) 4 
weeks as one cycle. Apatinib was administered until disease progression, death, consent withdrawal, 
unacceptable toxicity after 50% dose of reductions. Besides apatinib, patients with HR+ were given 
endocrine therapy (ET) at the same time. Apatinib was partially provided by the sponsor, Jiangsu 
HengRui Medicine Co., Ltd. 
Apatinib dose will be allowed to reduce to 250 mg/d if patients experience the following 
conditions: grade 3/4 of hypertension, nausea, vomiting, proteinuria and diarrhea; grade 4 
hematologic adverse events (AEs); other grade 3/4 non-hematologic AEs when investigators 


considered dose reduction necessary.  
 
Study design and assessments 
This was an open-label, single-arm, phase II study conducted at four centers in China. The 
primary end point was progression free survival (PFS), defined as time from the date of enrollment 
(first-dosing) to first documented tumor progression or death of any cause, whichever occurred first. 
Secondary end points included objective response rate (ORR), overall survival (OS), disease 
control rate (DCR), safety and tolerability. ORR was defined as the proportion of eligible patients 
who achieved a confirmed CR or PR by RECIST 1.1 criteria evaluated by the investigators. OS was 
defined as time from the date of enrollment to the date of death of any cause or the last follow-up 
visit. DCR was defined as the proportion of patients who achieved CR, PR and SD for at least 8 
weeks. Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles (8 weeks) 
thereafter until disease progression. Follow-up was done every 2 months until death or end of study. 
AEs were assessed and graded according to the US National Cancer Institute Common 
Terminology Criteria for AEs (CTCAE), version 4.03. The safety evaluation was continued until 28 
days after the last dose or recovery to grade 1 or 0 from any acute toxicities associated with apatinib. 
 
Statistical analysis 
All statistical analyses were performed using SPSS version 17.0 (IBM, Chicago, IL). Median 
PFS (mPFS) were calculated using the Kaplan–Meier method. Safety data were summarized 
descriptively using data from all patients who received at least 1 dose of study treatment and had at 
least 1 post-baseline safety evaluation. 
PFS and OS for patents who had at least 8 weeks treatment of apatinib were estimated using 
Kaplan–Meier method (unless progression during 8 weeks). Log-rank tests and Cox regression 
models were used for univariate and multivariate survival analysis of prognostic factors, and p <0.05 
was considered statistically significant.