Low-dose Apatinib Combined With Neoadjuvant Chemotherapy in the Treatment of Early Triple Negative Breast Cancer

Study Overview
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Brief Summary
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Triple-negative breast cancer (TNBC) is a special type of breast cancer, endocrine therapy and targeted therapy are completely ineffective, chemotherapy is currently the only effective treatment. How to improve postoperative pathologic complete response（pCR）of neoadjuvant chemotherapy is critical problem to prolong event-free survival (EFS) and overall survival (OS) of TNBC patients. Apatinib is a new oral small molecule tyrosine protease inhibitor, it is effective in inhibiting angiogenesis with a very low concentration. So the standard neoadjuvant chemotherapy regimen of docetaxel and carboplatin combined with apatinib may improve the postoperative pCR and survival outcomes of TNBC patients. Safety and tolerability assessed by number of grade 3 and 4 toxicities and hospitalizations.

Detailed Description
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All enrolled patients were administered oral apatinib at a dose of 250 mg once daily and intravenously docetaxel (100 mg/m2) every three weeks for four cycles, followed by epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) every three weeks for four cycles. All the treatments were continued until disease progression, patient withdrawal, or unacceptable toxic effects. Granulocyte colony-stimulating factor (G-CSF) used for prophylaxis of febrile neutropenia was permitted according to the American Society of Clinical Oncology (ASCO) guidelines. The biochemical and hematological indexes were evaluated every cycle. Dose modifications of chemotherapy agents, including dose interruptions and dose reductions, were permitted due to certain adverse events.

Official Title
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Low-dose Apatinib Combined With Neoadjuvant Chemotherapy in the Treatment of Early Triple Negative Breast Cancer (LANCET): A Multicenter, Single-arm, Phase II Trial

Conditions
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Triple-Negative Breast Cancer

Intervention / Treatment
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* Drug: Apatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or pathologically confirmed noninflammatory Triple-Negative invasive breast carcinoma (TNBC). The diagnosis of TNBC was defined below: the estrogen receptor and progesterone receptor negativity rates were less than 10%, and the human epidermal growth factor receptor type 2 (HER2) staining was 0 or 1+, and fluorescence in situ hybridization (FISH) detected no HER2 gene amplification Clinical stage IIA-IIIB Patients must have measurable disease as defined by palpable lesion with caliper and/or a positive mammogram or ultrasound. Bilateral mammogram and clip placement is required for study entry. Baseline measurements of the indicator lesions must be recorded on the Patient Registration Form. To be valid for baseline, the measurements must have been made within the 14 days if palpable. If not palpable, a mammogram or MRI must be done within 14 days. If palpable, a mammogram or MRI must be done within 2 months prior to study entry. If clinically indicated, x-rays and scans must be done within 28 days of study entry. Eastern Cooperative Oncology Group(ECOG) performance status 0 to 1 within 14 days of study entry Signed informed consent Adequate organ function within 2 weeks of study entry: Absolute bone marrow function (hemoglobin concentration of ≥8.0 g/dL, white blood cell count of ≥3000 cells per μL, absolute neutrophil count of ≥1500 cells per μL, platelet count of ≥70000 cells per μL), adequate renal function (creatinine was the upper limit of normal or lower), and adequate liver function (total bilirubin was the upper limit of normal or lower, and aspartate aminotransferase or alanine aminotransferase was twice the upper limit of normal or lower) Patients must be aged 18-70 years Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Exclusion Criteria: Metastatic disease Prior chemotherapy, hormonal therapy, biologic therapy, investigational agent, targeted therapy or radiation therapy for current breast cancer. Patients with history of breast cancer greater than 5 years from initial diagnosis are eligible for the study. Patients may not have received anthracycline-based chemotherapy in the past. Patients with history of ductal carcinoma in situ(DCIS) are eligible if there were treated with surgery alone History of previous or current malignancy at other sites with the exception of adequately treated carcinoma in-situ of the cervix or basal or squamous cell carcinoma of the skin. Patients with a history of other malignancies, who remain disease free for greater than five years are eligible Uncontrolled blood pressure, previous exposure to apatinib, known allergies to any of the excipients, and a history of unstable angina, myocardial infarction, or class III/IV congestive heart failure (defined by the New York Heart Association) within the past 6 months before day 1 of the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Group<br>Four cycles of docetaxel combined with apatinib followed by four cycles of epirubicin and cyclophosphamide as Neoadjuvant Treatment for Triple-Negative Breast Cancer | Drug: Apatinib<br>* All enrolled patients were administered oral apatinib at a dose of 250 mg once daily and intravenously docetaxel (100 mg/m2) every three weeks for four cycles, followed by epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) every three weeks for four cycles. All the treatments were continued until disease progression, patient withdrawal, or unacceptable toxic effects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pathological complete response (pCR) rate in the breast and lymph nodes (ypTis/0ypN0) | Absence of invasive tumor cells in the breast and lymph nodes and was determined by a local pathologist | up to 24 weeks (at the end of cycle 8, each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR was assessed according to RECIST version 1.1, which included patients with measurable disease who achieved a complete or partial response of target lesions. | up to 24 weeks (at the end of cycle 8, each cycle is 21 days) | 
| Event-free survival (EFS) | The interval from the start of treatment to progression prior to surgery, post-surgery recurrence, or death due to any cause | up to 24 months | 
| Overall survival (OS) | The time from registration to death from any cause | up to 24 months | 
| Adverse events | The treatment-related adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE 4.0). | up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple-Negative Breast Cancer, apatinib, pCR, OS, Neoadjuvant chemotherapy