Combined use of apatinib mesylate and vinorelbine versus single use of vinorelbine in recurrent or metastatic triple-negative breast cancer: study protocol for a randomized controlled clinical trial

Background: The emergence of new molecular targeted drugs provides new prospects for the treatment of advanced breast cancer; the future therapeutic trend includes chemotherapy combined with molecular targeted therapy. Apatinib mesylate, a novel, small anti-angiogenic agent, highly selectively inhibits the activity of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib mesylate also blocks the signaling of vascular endothelial growth factor binding to its receptor, thereby, strongly inhibiting tumor angiogenesis and exerting an anti-tumor effect. However, a randomized controlled clinical trial of apatinib combined with vinorelbine for triple-negative breast cancer (TNBC) has not been reported. We will compare the therapeutic effect of vinorelbine alone or in combination with apatinib mesylate in patients with recurrent or metastatic TNBC in North China who have received at least two drug treatments including anthracyclines and taxanes. Methods/analysis: This study is a triple-blind, randomized, placebo-controlled, parallel-group clinical trial. We plan to include 164 female patients with locally recurrent or metastatic TNBC and without BRCA1 mutation (as BRCA -positive patients would have poor responses to the therapeutic methods designed in this study), admitted at the Liaoning Cancer Hospital & Institute, Northeast China. All enrolled patients will be randomized to orally take vinorelbine alone (40 mg orally, thrice a week (Mondays, Wednesdays, and Fridays) in each 3-week cycle) or combined with apatinib mesylate (500 mg orally, once daily of each 3-week cycle). Radiographic assessment will be performed every 6 weeks for 36 weeks, and every 9 weeks thereafter. The primary outcome is measurement of progression-free survival and secondary outcomes include overall survival, disease control rate, objective response rate, and incidence of adverse events at grades 3 and 4 as defined by the National Cancer Institute Common Toxicity Criteria [NCI-CTC] Version 4.0. Outcome measures will be evaluated at baseline (< 2 weeks before RECIST: Response Evaluation Criteria Solid Overall Disease control SARs: serious drug-induced liver Independent Data Monitoring Data

starting treatment), every 6 weeks during treatment, and at 4 weeks and every 3 months after treatment discontinuation. Discussion: Based on the data from this trial, we hope to identify a treatment plan that is suitable for female TNBC patients in Northeast China who have been treated with anthracyclines and taxanes. Trial registration: ClinicalTrials.gov (identifier: NCT03932526). Registered on April 30, 2019.

Background
The International Agency for Research on Cancer predicts that the number of cancers in the future will increase at an annual rate of 3-5%. It is estimated that there will be 20 million new cases worldwide until 2020, and the number of deaths will reach 12 million.
The incidence of cancer in low-and middle-income countries is extremely higher than that in developed countries [1]. Breast cancer is one of the malignant tumors with high prevalence in women and a common cause of death. Annually 13 million people are newly diagnosed with breast cancer, and about 400,000 people die of breast cancer with a mortality of 20-30%. In developing countries, breast cancer has become the leading cause of death in women [2].
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER-2), which accounts for 10-17% of all breast cancers [3]. TNBC is characterized by high heterogeneity, high invasiveness, low survival rate, early recurrence and metastasis, lack of effective treatment, and poor prognosis [4,5].
Despite significant advances in breast cancer treatment, approximately 15% of breast cancer patients are diagnosed at an advanced stage. According to staging, grading, and choice of treatment, 20-80% of all invasive breast cancer patients will eventually relapse and require a subsequent treatment [6]. Chemotherapy is the main treatment for early and advanced breast cancer, and the most effective drugs include anthracyclines and taxanes [7]. However, the increasing use of anthracyclines and taxanes in the early stage of the disease makes the choice of a second-line therapy difficult, and drug resistance often limits the choice of treatment regimens [8]. Endocrine therapy, anti-HER-2 targeted therapy and chemotherapy cannot achieve satisfactory outcomes in TNBC, as there is no corresponding hormone receptor or HER-2 expression. Some progress has been made in the field of TNBC therapy regarding the use of immunological checkpoint inhibitors. PD-1/PD-L1 monoclonal antibody, the most common immunological checkpoint inhibitor, that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells. PD-1/PD-L1 activates immune cells and then kills tumor cells. Currently, only PD-L1 monoclonal antibody -Atezolizumab (Tecentriq®) and PD-1 monoclonal antibody -Pembrolizumab (Keytruda®) have been approved for use by the US FDA. The combination of Pembrolizumab + chemotherapy as neoadjuvant therapy for early TNBC can significantly improve pathologic complete remission [9]. Relative to chemotherapy, pembrolizumab is used as a second-or third-line treatment for metastatic TNBC patients, but it does not significantly improve overall survival (OS) [10].
IMpassion130, a clinical phase III double-blind randomized trial reported in 2016 [11], and the updated data from IMpassion130 until 2019 [12] indicated that the combination of Atezolizumab (Tecentriq) and albumin paclitaxel as first-line treatment for advanced TNBC yields a better progression-free survival than the use of paclitaxel + placebo.
Unfortunately, no approval has been given for clinical trials on checkpoint inhibitors for TNBC in China; furthermore, no such drug is available in clinical practice. Therefore, this study was designed to determine the effect of the combination of apatinib (a smallmolecule anti-angiogenic targeted drug) and vinorelbine (a semi-synthetic vinblastine alkaloid antineoplastic drug), two types of drugs that have been used clinically in China, in the treatment of TNBC.
Combination chemotherapy with vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) target inhibitors is one of the most promising regimens for advanced breast cancer [13]. Apatinib mesylate (Aitan) is a novel, small anti-angiogenic agent that highly selectively inhibits the activity of VEGFR-2 tyrosine kinase, and blocks the signaling of VEGF binding to its receptor. Thus, it strongly inhibits tumor angiogenesis and exerts anti-tumor effects. The clinical use of apatinib in breast cancer has also been reported, but the relevant research focuses on its safety and efficacy in breast cancer patients with different hormone receptor expressions [13,14]. As reported, apatinib at an initial dose of 750 mg/day or 500 mg/day was used in TNBC patients. The mean progression-free survival (mPFS) and mean OS (mOS) were 4.6 and 8.3 months for the former dose; and 3.3 and 10.6 months for the latter dose, respectively [14]. In advanced breast cancer, oral treatment with apatinib was used after first-line or second-line treatment failure. The objective response rate (ORR) was 40.0%, the disease control rate (DCR) was 75.0%, and the median time to progression (mTTP) was 12 months [13].
Vinorelbine is a semi-synthetic vinblastine alkaloid antineoplastic drug, mainly used for the treatment of non-small cell lung cancer and metastatic breast cancer. A previous multi-center clinical trial [15] used vinorelbine combined with cisplatin, capecitabine, or tegafur for the treatment of recurrent and metastatic breast cancer that occurred after treatment with anthracyclines and taxanes. The effective rate was 61.0%, with a complete response (CR) of 4.9%. This combination therapy was highly effective for multiple and single metastatic lesions, and moreover, the therapeutic efficacy was better in multiple metastatic lesions. The short-term effect was fair, with tolerance to toxicity and good safety. Studies have reported the use of vinorelbine combined with 5-fluorouracil for the treatment of advanced metastatic breast cancer, which anthracycline/taxane fails to treat, and the effective rate is 17.4-46% [16][17][18]. In patients with metastatic TNBC, vinorelbine or gemcitabine combined with cisplatin is preferred after failure in the treatment with anthracycline/taxane. The existing results have shown that the objective and effective rates of the experimental group and the control group were 45.45% and 46.15%, respectively, and the DCRs in the two groups were 77.27% and 80.77%, respectively. In the experimental group, the time to progression (TTP) was 2.0-18.0 months, with the mTTP of 5.0 months (95% confidence interval [CI]: 3.28-6.72). In the control group, the TTP was 1.8-18.5 months, with the mTTP of 5.2 months (95% CI: 3.33-7.07) [19].

Study features and objectives
Currently, there are cohort studies [20][21][22], retrospective observations [23][24][25][26], and case reports [27,28] addressing the clinical treatment of TNBC with apatinib or vinorelbine (Table 1). However, a randomized controlled clinical trial of apatinib combined with vinorelbine for TNBC has not been reported in North China. As BRCA-positive patients would have poor responses to the therapeutic methods designed in this study. BRCAnegative female locally recurrent or metastatic TNBC patients in North China who have previously received anthracyclines and taxanes for the adjuvant treatment of metastatic disease will be the target population in this trial. We will compare the therapeutic effect of vinorelbine used alone or combined with apatinib mesylate for the treatment of recurrent or metastatic TNBC patients who have at least received one chemotherapy regimen, including anthracyclines and taxanes, to provide clinical evidence for multi-line treatment options for advanced TNBC.

Study design
This study is a triple-blind, randomized, placebo-controlled, parallel-group clinical trial.
A population of 164 female BRCA-negative patients with recurrent or metastatic TNBC who have been pretreated with at least one chemotherapy regimen, including anthracyclines and taxanes, will be recruited (as BRCA-positive patients would have poor responses to the therapeutic methods designed in this study, we excluded BRCA-positive patients (11% of the 184 patients) from the study based on our clinical experience and previous study findings [29]). According to the Consolidated Standards of Reporting Trials (CONSORT) [30], the baseline, therapeutic schedules, and outcomes of enrolled breast cancer patients will be recorded, and patients' data in each center will be collected by electronic data capture system (EDC).
All enrolled patients will be randomly assigned to receive either oral apatinib mesylate in combination with vinorelbine or oral vinorelbine plus placebo until disease progression or other criteria for administration termination. A schedule of enrollment, interventions, and assessments is shown in Figure 1 and a trial flowchart is shown in Figure 2. The study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting (Additional file 1) [31].

Subjects
The required female patients with breast cancer for the trial will be recruited from   [32], there is at least one measurable lesion. For non-lymph nodes, at least one lesion has the longest diameter > 1.0 cm; or for lymph nodes, at least one lesion has a minor axis diameter > 1.5 cm.
-All patients will be tested for bone marrow capacity, liver, and renal functions within 7 days prior to enrollment and will meet the following aspects: 1.
-Previous use of anthracyclines and/or taxanes -The medication history of vinorelbine meets one of the following conditions: 1. Never or irregular use of vinorelbine (the standard use of vinorelbine is defined based on the appropriate use of the medication as prescribed, for at least two cycles);

2.
Advanced breast cancer patients, who undergo the standardized medication of vinorelbine for 6 months and have no progression, and who have not used vinorelbine within 6 months prior to the first administration.
-Female patients of childbearing age must take adequate contraception; otherwise they must be proven to be infertile, that is: 1.
Patients over the age of 50 are confirmed to have menstruation-deficient menopause for at least 12 months after stopping all exogenous hormone treatments;

2.
Under the age of 50; on this basis, it is also necessary to prove that the levels of The recruitment conditions for the trial will be publicized at the outpatient and inpatient departments. Patients interested in the trial can contact the project leader by telephone, email or WeChat through their attending doctor.
Recruitment conditions will be publicized at a strategic location or on a bulletin board.
Patients interested in the trial can contact the project leader using the advertised contact details.
Patients who agree to participate in the trial will be asked to sign informed consent form prior to enrollment in the trial.

Randomization
Randomization will be performed by a professional, independent statistician who will not be involved in the recruitment process of the study. The statistician will use the Statistical Analysis System (SAS 9.1) software to generate a randomization sequence list, and assign each patient a serial number to complete the randomization. Sequence numbers will be sealed in opaque envelopes prepared by research assistants who will not be involved in the recruitment process. These envelopes will be saved in a double-locked cabinet by another investigator who will not be involved in the trial.

Blinding
At the beginning of the study, nurses who will not participate in the trial will randomly dispense drugs to eligible patients based on their allocation sequence. All patients, investigators, and data analysts will be unaware of the grouping information until the end of the trial. A binding test [34] will be performed to ensure that each patient is blinded to the grouping information. In case of emergency, the investigators can urgently determine the medication of the patients to ensure that the patients will receive timely and correct medical treatment.

Drug administration
Vinorelbine plus apatinib group: Combined administration of vinorelbine and apatinib. Vinorelbine plus placebo group: Based on oral administration of vinorelbine, the patients will be given oral placebo (starch as an ingredient). The placebo appearance, including shape, size, color and weight, taste, labeling and packing are the same with those of apatinib mesylate tablets.
The placebo and apatinib will be manufactured by Jiangsu Hengrui Pharmaceutical Co., Ltd., China in accordance with the guidelines of Good Manufacturing Practice (Chinese Edition). The manufacturer will have no direct involvement in the study (apart from the drug manufacturing and delivery to the clinical trial centers).
An assessment will be conducted every two cycles of the above administration protocol for chemotherapy until unacceptable toxicity, disease progression, or investigator decision.

Apatinib
Principle for dose adjustment: In the case of adverse reactions associated with apatinib, the dose of apatinib will be first adjusted ( Table 2). There are two dose levels of apatinib: 1) initial dose: 500 mg, once daily; 2) secondary dose: 250 mg, once daily. Medication will be paused if the patients cannot recover from drug toxicity. The time for each pause and the cumulative time of overall pauses per cycle are restrained not to exceed 1 week.
There is a maximum of two pauses per cycle, to ensure the medication intensity in each patient (such patient who cannot meet the above criteria or a delay of the next cycle of treatment for over 2 weeks will be required to terminate the trial).
The medical dose will be adjusted at any time during each dosing cycle. Once the dose is reduced, it is not allowed to increase it to the previous level. Not more than one dose adjustment is allowed for each subject. After the dose is down-regulated to 250 mg, no further dose adjustments are allowed, including up-or down-regulation for any reason.
However, pausing of administration is still permitted.

Vinorelbine
Drug withdrawal and re-administration: When any condition that is compliant with the criteria for drug withdrawal occurs, administration of vinorelbine will be discontinued. If the patient meets the criteria for drug re-administration in all of the subsequent cycles, the administration of vinorelbine will be resumed, but the doses that are not taken during the withdrawal period would not be replenished ( Table 3).

Concomitant medications
Other anti-tumor drugs not approved by this protocol would be discontinued during the administration of drugs in this trial.
Conventional medications can be given symptomatically, including prophylactic antiemetics and treatment with granulocyte colony-stimulating factor for the reduction in the patient's hemogram. Hematopoietic growth factor support is permitted to avoid treatment interruption or delay. All symptomatic medications should be documented and detailed on a case report form.
Alcoholic drinks should be avoided during treatment.

Baseline evaluations (conducted within 2 weeks of the start of protocol therapy)
Sign an informed consent Every 3 months after treatment discontinuation until a patient dies or the study closes: During the follow-up period, ECOG-PS score, the start of new anticancer treatment(s), and subsequent disease progression, the survival status will be assessed. Tumor treatment is also considered to be tumor progression. For patients who have not progressed or died of disease at the end of the study, the time for no disease progression recorded at the last follow-up is used as censored data.

Secondary outcomes
-OS indicates the length of time from enrollment to death from any cause. When no information on death is collected in the clinical database, the last date when the patient is still known to have survived is used as the cut-off point.
-DCR indicates the percentage of patients with CR, partial remission (PR), and disease stabilization; and maintenance over 4 weeks, accounts for all the subjects with evaluable efficacy.
-ORR is the proportion of patients who achieve a CR or PR ((CR+PR)/total number of cases × 100%), as assessed by the RECIST v1.1 [32].
-Adverse events at levels 3 and 4: Patients with adverse events at levels 3 and 4 will be assessed according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 4.0 [35].

Other measures
-Quality of life will be assessed using the EORTC QLQ-C30 version 3.0 [36]. The scores have to be averaged and transformed linearly to obtain a range of scores, from 0 to 100, with higher scores meaning a great response level.
-General health status is assessed using the ECOG-PS scale [37]. The scale divides the patient's activity status into 0-5 levels. A higher level indicates a worse physical status.

Adverse events
All adverse events should be recorded appropriately in a case report form and assessed by the investigators according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. [35] If the level of alanine aminotransferase or aspartate aminotransferase is ≥ 3 × ULN or total bilirubin ≥ 2 × ULN, a serious adverse event (SAE) report may be necessary. The investigators must promptly determine whether the patient meets the Hy's Law (druginduced liver injury [DILI]), without delay.
The investigators should assess the causal relationship between adverse events and target drugs. The decisive factor in the assessment is the temporal correlation between the adverse event and target drug. All deaths occurring during the study period or during the last follow-up period (30 days after the last dose) or until the disease progression (whichever occurs later) must be reported.
The investigator is obliged to immediately call or fax or email information on any serious or medically significant clinical adverse events or laboratory abnormalities during the study period, regardless of treatments received by the subject, to the Adverse Drug Reaction Monitoring Center, the sponsor, and the Ethics Committee within 24 hours.
The most adequate supportive therapy will be given for hematological toxicity, nonhemotoxic diarrhea, liver toxicity, and peripheral neurotoxicity. If the symptoms are relieved immediately after the supportive treatment, it is medically acceptable to continue with the appropriate treatment. If the investigator believes that the treatment is beneficial to the patient, the same dose of the drug plus corresponding supportive treatment will be continued. A medical reduction will be allowed as required. The study will be terminated if the medication, due to an adverse event, is delayed for more than 21 days.

Criteria for re-administration/cycle delay
Patients who meet all of the following criteria can receive the planned treatment: Absolute neutrophil count > 1500/mm 3 Platelets > 100,000/mm 3 Treatment-related non-hematologic toxicity has been eliminated at baseline or ≤ level 1 (except for level 2 alopecia or level 2 fatigue).
If the patient cannot meet the criteria, the planned treatment should be delayed.
Re-evaluate the patient's conditions at least once a week.
The medication on the 8th day of each cycle cannot be delayed for over 1 week, otherwise, the medication will be cancelled. The medication time of the next cycle will not change.
If there is failure of recovery from treatment-related toxicity to baseline or level 1 (except level 2 and level 2 fatigue) within 3 weeks as scheduled (i.e., the start of each new cycle is delayed for over 21 days as compared with the scheduled time), the patient will withdraw from the trial.
For patients who are effective in the treatment, they can continue to use the drug with the consent of the sponsor.

Participant withdrawal
Patients will be withdrawn from the study if they: (1) withdraw informed consent, (2) request to withdraw from the trial, and (3) decline to continue treatment or follow-up.
All source data and source files related to all withdrawn participants will be retained. The time and cause of withdrawal will be recorded on the case report form in detail.

Monitoring
Progression of the trial, adverse events, and data quality will be monitored by an Independent Data (and safety) Monitoring Board (IDMB) independent of the trial sponsor.
The IDMB will be responsible for reporting the security data in the trial to the primary investigator. The primary investigator will submit a list of all suspected SAEs to the Independent Ethics Committee (IEC), as well as a summary of all reported SAEs every 6 months.

Audits
An inspector will review the incoming data monthly and generate a data query if necessary. The inspector will review whether each electronic case report form is completed accurately. All discrepancies in the electronic case report form will be corrected by the investigator or authorized personnel in an appropriate manner.

Data management
Data entry and management are the responsibility of an independent data administrator using the EpiData 3.1 software (The EpiData Association, Denmark, Europe). In order to ensure the accuracy of the data, the data will be input and proofread using a double-data entry strategy by two data administrators independently. The data administrators will list the questions in the case report form in the Data Request Queue (DRQ); and the investigator will respond and return as soon as possible. The data administrators will then modify, confirm, and enter the data according to the investigator's responses. Another DRQ can be submitted if necessary. All original files will be kept in accordance with the deadlines set by the Good Clinical Practice of China, and clinical data will be kept by the investigators for 5 years, starting from the end of the clinical trial. All the clinical data of this trial will be the property of the sponsor, and the investigators will have no right to disclose these data to a third party without written approval by the sponsor.

Sample size
Based on previous experience [38] and pilot study results, the mPFS was estimated to be 4.4 months in the vinorelbine monotherapy group and 6.7 months in the vinorelbine + apatinib group. The recruitment time is expected to be 26 months and the follow-up time is planned for 15 months. Taking α = 0.05 (two sides) and β = 0.25, the required sample size of 168 was calculated if the subjects in the two groups are enrolled basically at a ratio of 1:1, using PASS 11 (NCSS Statistical Software, Kaysville, Utah, USA). Assuming a loss rate of 10% for the lost-to-follow-up cases, a total sample size of 184 will be required.

Statistical analysis
Analysis of the primary and secondary outcomes will be performed according to an intention-to-treat (ITT) and a per-protocol (PP) basis. The method of last observation carried forward (LOCF) will be carried out for imputing missing values. Additionally, sensitivity analysis will be used to evaluate the impact of missing data on the trial results.
No interim analysis will be performed.
Statistical analyses will be performed by a statistician using SPSS 22.0 software (IBM, Armonk, NY, USA). Continuous variables will be statistically expressed as the mean, standard deviation, median, minimum, and maximum, while categorical variables will be expressed as numbers and percentages.
Descriptive statistics will be performed on feature data at baseline. For categorical variables, DCR, ORR, and the incidence of adverse events will be compared between groups using the Spearman's chi-square test or Fisher's exact test. For continuous variables, PFS, OS, EORTC QLQ-C30 score, ECOG PS score, and laboratory indicators will be compared between groups using an independent sample t-test or Mann-Whitney U test.
All statistical analyses will be performed based on a two-sided test. A P value of ≤ 0.05 will be considered statistically significant and the 95% CI will be calculated.
Survival data (PFS and OS) will be estimated using the Kaplan-Meier method. Differences between grouped survival profiles will be assessed with the Log-rank test. Factors influencing survival (that is, age, TNM staging, tumor differentiation status, lymph node metastasis, and chemotherapy cycles) will be analyzed using the Cox proportional hazard regression analysis. Results are expressed in hazard ratios (HR) and 95% CIs.

Quality control
The clinical research unit must provide a clinical research base for drugs research with clinical research conditions as determined by the National Medical Products Administration of China. Investigators must be clinically trained physicians who work under the direction of a senior professional. Pre-test clinical wards must meet the requirements of standardization to ensure that rescue equipment is fully functional. Each subject will be given medications by professional caregivers in order to learn more about the medications taken, ensuring the subject's compliance. The study protocol must be strictly executed in the research center, and the case observation form should be filled out truthfully. The standard operating rules of clinical trials should be followed and implemented in the research center. All the clinical procedures will be supervised, all data record will be con confirmed that they have been reported correctly and completely; and all case report forms are correctly filled out and consistent with the original data. In the event that an SAE occurs in the research center, it will be promptly reported to each research unit and, if necessary, the trial will be temporarily discontinued.

Ethics and informed consent
-The trial will be performed in accordance with the following conditions: 1) the study protocol, written informed consent, data to assist in the participation and compensation measures for the subject will be fully approved by the IEC; 2) the sponsor will receive a copy of the IEC approval document. A supplement scheme that increases the risk to the subjects and corresponding modified informed consent will be timeously submitted to the IEC for review, and this scheme will be implemented after approval by the IEC. This research plan refers to protocol V2.0.
-Written informed consent will be given by each subject prior to the participation in the trial. The investigators will be responsible for the complete and comprehensive introduction of the study purpose, roles of drugs used, possible side effects and risks to the subjects or their designated representatives. The subjects will be informed of their right, risks assumed and benefits. The investigator will inform the participants that participation in the study is voluntary and that they can withdraw at any time. Finally, it will be ensured that subjects understand that the investigator will maintain their records for long-term follow-up, and that their records may be viewed by relevant management officers, within the limits of relevant laws and regulations. Subject's privacy will be protected.

Dissemination
The final research results will be disseminated through publications in peer-reviewed academic journals or at international academic conferences.

Protocol amendments
All amendments to the protocol will only be signed and dated by the Department of Breast Medicine, the Liaoning Provincial Cancer Hospital, China, approved by the IEC, before release. There should be no protocol deviation during the study, but the investigator should promptly deal with it if or when it occurs. In the case report form and in the original case report, the protocol deviation and the protocol deviation table, and its reasons will be recorded. These will be saved in the research unit by the sponsor.

Principle of confidentiality
During the collection and use of patients' data, full patient confidentiality will be maintained with compliance with relevant laws and regulations that protect the subjects' privacy. The investigator will obtain the consent of each subject prior to the collection of personal data. The subject has the right to obtain his/her personal data through the investigator, and to modify the errors or incomplete data. Not all personal information will be obtained nor disclosed to unauthorized others; these will not be destroyed accidentally or illegally, neither will it be lost or altered accidentally. Throughout the study period, the sponsors with access to the subjects' personal data will keep such confidential.

Compensation
Fund for drug therapy will be provided by the pharmaceutical company manufacturing the target drugs; they have no role in the study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.
Each patient having provincial, municipal, remote, or new rural cooperation medical insurance will be subsidized with RMB 600 yuan (~85.5 USD) after completing one chemotherapy cycle. Self-paying patients will be given the next cycle of chemotherapy free (chemotherapy drugs only) after each cycle of chemotherapy.
Compensation mechanism: The specific compensation standards and methods will be clarified before the trial, and the sponsor will provide the Clinical Trial Insurance for each subject. Treatment cost for drug-related adverse events and corresponding economic compensation will be undertaken by the sponsor. Based on the data from this trial, we hope to identify a treatment plan that is suitable for female TNBC patients in Northeast China who have been treated with anthracyclines and taxanes, which is of great clinical significance.

Availability of data and materials
The results of this study will be disseminated via peer-reviewed publications and conference presentations. No data are available at the moment.

Authors' contributions
TS and SW conceived the study and participated in its design and coordination. SW drafted and wrote the manuscript. LZ and HL participated in the design of the study and performed the statistical analysis. JX and CJ participated in the study design and coordination and helped draft the manuscript. All authors read, revised and approved the final manuscript.

Ethics approval and consent to participate
The trial will be conducted in accordance with the guiding principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the Liaoning Provincial Cancer Hospital (approval No. 20180948-2) in October 2018. All patients will provide written informed consent prior to the participation in the trial.

Consent for publication
Not applicable.  Drug administration will be paused at level 3 and will be continued at the ini when the NCI level is restored to ≤ level 2. If NCI ≥ level 3 occurs aga administration at secondary dose will be continued. 4 Drug administration will be paused at level 4 and will be continued at the second when the NCI is ≤ level 2.
Non-hematologic adverse reactions 3 Drug administration will be paused at level 3 and will be continued at the ini when the NCI is restored to ≤ level 1. If the NCI ≥ level 3 occurs aga administration at the secondary dose will be continued. 4 Drug administration will be paused at level 4 and will be continued at the second when the NCI is ≤ level 1. Drug withdrawal and re-administration will be assessed using the National Cancer Institute Supplementary Files