Primary outcome
PFS refers to the length of time from random enrollment to any recorded tumor progression or death from any cause. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, tumor conditions during the treatment and follow-up periods will be evaluated. If the patient has several indicators that can be judged as progression of disease, the PFS analysis will be performed based on the indicators that first emerged. Recurrence, presence of new lesions, or death is considered as having reached the end of the study. The use of other systemic or targeted anti-tumor therapy will also be considered as tumor progression. 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 collected at the last follow-up is used as censored data.
Secondary outcomes
- Overall survival (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.
- Disease control rate (DCR) indicates the percentage of patients with CR, partial remission, and disease stabilization; and maintenance over 4 weeks, accounts for all the subjects with evaluable efficacy.
- Overall remission rate (ORR) is the proportion of patients who achieve a complete or partial response ((CR+PR)/total number of cases x 100%), as assessed by the RECIST v1.1 [27].
- 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 [30].
Other measures
- Quality of life will be assessed using the EORTC QLQ-C30 version 3.0 [31]. 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 [32]. The scale divides the patient's activity status into 0-5 levels. A higher level indicates a worse physical status.
- Laboratory examination: (1) Hematology: hemoglobin, white blood cell count, neutrophil count, and platelet count; (2) blood biochemical tests: total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum creatinine, total protein, sodium ion, potassium ion, blood magnesium, chloride, blood calcium, blood urea; and pregnancy test (if applicable); (3) tumor marker detection: CA153 and CEA.
Adverse events
Definition of adverse events
- Adverse events: An adverse event refers to any adverse medical event that occurs after a patient or clinical study subject takes a drug. This event does not necessarily have a causal relationship with the treatment. Therefore, the adverse event can be any bad or unintentional signs, including abnormalities in laboratory findings, symptoms, or transient drug-related diseases, which should be considered whether it is related to medication. Adverse events that occur before and after treatment will all be included. A safety monitoring to report adverse events or serious adverse events (SAEs) should be ensured from the enrollment of subjects to the end of the study. Therefore, adverse events that occur during the signing of informed consent and the initiation of study treatment will also be included.
- Adverse drug reactions: Any toxic and unintended reaction to a drug associated with any dose should be considered an adverse drug reaction. The response to the drug means that there is at least a reasonable possibility of causality between the drug and the adverse event, which means that this relationship cannot be excluded.
- SAEs or serious adverse reactions (SARs): An SAE or an SAR indicates any adverse medical event that occurs to any drug dose. When an SAE occurs, the subject is at risk of death rather than assuming a more serious event resulting in death; if the SAEs occur, the subject needs to be hospitalized or the length of existing hospitalization should be extended; or any adverse event resulting in sustained or significant loss of ability/disability.
- Important medical events: A medical and scientific accreditation is required to determine the appropriateness of a prompt medical report in the case of an important medical event. These important medical events may not immediately threaten life or result in death or hospitalization, but they may harm the subject, or an intervention may be required to prevent the occurrence of the aforementioned results. Usually the following events should also be considered serious, such as some adverse events in the emergency department requiring critical care and treatments, or allergic bronchial asthma at home; dyscrasia or convulsions that do not require hospitalization; drug dependence and abuse, or malignant tumors histologically different from primary tumors.
- Other events that should be treated as SAEs: Drug exposure during pregnancy/lactation. In principle, pregnancy and lactation are included in the exclusion criteria. If a pregnancy occurs during the study period, the patient should immediately withdraw from the study and should immediately inform the investigators. The investigators should follow up the patient throughout pregnancy and postpartum. Even if the mother and child are completely normal without any adverse events, the consequences should be recorded. Even if the pregnancy does not fit into an SAE, it should be reported in the SAE report form.
- Events that should not be treated as SAEs: Disease progression does not fit into an SAE.
Recording and evaluation of adverse events
All adverse events should be recorded appropriately in a case report form. In addition, an SAE report form (including initial or follow-up reports) should also be completed.
The following aspects of each event will be documented in the case report form: the adverse event will be described in medical terms, not as subjects, including date of occurrence (initial date), time of occurrence (start time), date of recovery (end date), recovery time (end time). The evaluation will be performed by the investigators according to the NCI-CTC version 4.0 [30]: level 1 = mild; level 2 = moderate; level 3 = severe; level 4 = life threatening or disabling; and level 5 = death.
If the level of alanine aminotransferase or aspartate aminotransferase is ≥ 3 x ULN or total bilirubin ≥ 2 x ULN, an SAE report may be necessary. The investigators must promptly determine whether the patient meets the Hy’s Law (drug-induced liver injury [DILI]), without delay. Diagnosis and treatment of DILI cases should be described. Such SAEs that occur up to 30 days after the last dose will be recorded.
The investigators should assess the causal relationship between adverse event and target drugs. The decisive factor in the assessment is the temporal correlation between the adverse event and target drug. The causal relationship between the adverse event and target drug (or study protocol) is judged as follows: irrelevant = there is no temporal relationship between the adverse even and target drug (drug medication is too early, too late, or not), or a reasonable causal relationship between the adverse event and another drug, concomitant disease or environment; impossible = there is a temporal relationship between the adverse event and target drug, but no reasonable causal relationship between the adverse event and the target drug; possible = there is a reasonable causal relationship between the adverse event and target drug, but with no or uncertain drug withdrawal (discontinuance) information; no doubt = there is a reasonable causal relationship between the adverse event and the target drug, with drug discontinuation or withdrawal having an effect on the adverse reaction, and no need to be proved by re-administration; definite/determined = there is a reasonable causal relationship between the adverse event and the target drug, with drug discontinuation having an effect on the adverse reaction and the adverse event occurring again after re-administration if clinically acceptable.
Consequences are defined as follows: (1) recovery with sequelae; recovery without sequelae; no recovery, but no need of treatment; no recovery, and treatment required; and death. (2) Whether the toxicity grade/severity has changed. If the same adverse event appears several times in the patient, it must be recorded and reassessed every time.
Treatments of dead cases
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 as follows:
- Deaths definitely resulting from disease progression must be reported to the research representative and must be recorded in the case report form but should not be reported as SAEs occurring during the study.
- If a death is not clearly attributed to the disease progression, the primary cause of death and the event most likely to result in death must be reported to the sponsor as an SAE within 24 hours. The report must contain comments on whether or not the disease is progressing at the same time and must identify a major cause of death and all contributory factors.
- If the cause of death is unknown, it must be reported as an SAE, but the cause of death still needs to be identified. An autopsy may be helpful in assessing the cause of death, and the autopsy results should be urgently reported to the sponsor within the specified time.
Reporting procedure for SAEs
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.
After oral report via telephone, the written source needs to be faxed. The report should provide information on the rapporteur and receiver, including name, address, telephone, and fax numbers; and indicate that it is a “preliminary” report or a “follow-up” report. If necessary, the relevant case report form should be accompanied. The investigator should ensure that the public ethics committee or the competent authority is provided with information on any additional requirements for the death of the subject.
Monitoring of adverse events in subjects
Any adverse events that occur during the study will be monitored and followed up until the end of the study. In addition, SAEs must be reported through the SAE form.
Treatments of adverse reactions
Any dose change should be documented for a clear cause. The most adequate supportive therapy will be given for all toxicities. 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.
- Hematological toxicity
The current cycle dose will be adjusted based on the lowest blood cell count after the last dose (Table 4):
If level 4 or 3 neutropenia with febrile neutropenia (> 38.5°C) or above level 3 thrombocytopenia occurs after two reductions, there is no longer a third reduction, and the investigator will determine whether the trial should be continued or not in accordance with specific conditions.
- Non-hemotoxic diarrhea including diarrhea with mucositis
The investigator will determine a reduction if non-hematologic toxicity (except vomiting and hair loss) such as diarrhea with mucositis of above level 3 appears.
- Liver toxicity
- Bilirubin: If bilirubin ≥ 1.5 times the ULN, the next cycle should be delayed. If the total bilirubin has not recovered to the ≤ 1.5 times the upper limit of normal for ≥ 3 weeks, the trial will be discontinued.
- Transaminases: Liver protection treatments will be taken if alanine aminotransferase and/or aspartate aminotransferase and/or alkaline phosphatase are at abnormal levels in the absence of the disease progression within 1 week. But if the abnormal level(s) still does not return to normal, the drug dose will be adjusted according to Table 5. In the next cycle, the dose should be increased to the initial level if the patient’s liver function recovers.
- Peripheral neurotoxicity
When level III-IV peripheral neurotoxicity occurs and the patient's life is seriously affected (the initial dose cannot be tolerated), the investigator will decide whether to reduce the dose by 20% or discontinue the drug.
Criteria for re-administration/cycle delay
Patients who meet all of the following criteria can receive the planned treatment:
- Absolute neutrophil count > 1500/mm3
- Platelets > 100,000/mm3
- 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.
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 [33] 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), 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%, the lost-to-follow-up cases, the final sample size of 184 will be required.
Statistical analysis
All validity indicators (PFS, OS, DCR, ORR) will be analyzed based on the full analysis set and the per-protocol set. According to the principle of intention-to-treat analysis, the full analysis set (the main analysis set for determining the efficacy of this trial) will include data of all subjects who will at least take the target drugs once. Per-protocol set will be the data of all cases who meet the criteria of the trial protocol, have good compliance, take at least one cycle of target drugs, do not take any banned drugs during the trial period, and have the complete lists to be filled out in the case report form. No imputation will be made for missing data. A safety analysis (incidence of adverse events) will be conducted on a safety analysis set, which will be the dataset of all enrolled patients who will at least take target drugs once, and have post-medication safety records. 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. Cox proportional hazard model will be used to assess the effects of variables on patients’ survival. Hazard ratios and the 95% CI will be recorded for each factor on the basis of intergroup differences (that is, age, TNM staging, tumor differentiation status, lymph node metastasis, chemotherapy cycles), which can identify the influence of competing risk factors for the outcome event. All reported P-values will be based on two-sided tests, and the CI will assume a significance of 0.05.
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 dissemination
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.
- The trial will be conducted in accordance with the guidelines of Good Clinical Practice, the guiding principles of the Declaration of Helsinki, as well as applicable local laws and regulations. The study protocol was approved by the Ethics Committee of the Liaoning Provincial Cancer Hospital in October 17, 2018 (approval No. 20180948-2) (Additional file 2) and the trial has been registered at ClinicalTrials.gov (identifier: NCT03932526). 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 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.