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Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Combining anti-angiogenesis with chemotherapy yielded increased response rates in patients with early-stage human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This study aims to evaluate the efficacy and safety of adding anlotinib to standard neoadjuvant chemotherapy in primary (HER2)-negative breast cancer. Patients aged 18 years or older with previously untreated stage Ⅱ-III histologically documented (HER2)-negative breast cancer were assigned to receive chemotherapy plus oral Anlotinib. The primary endpoint was pathologic complete response (pCR) (no invasive carcinoma in breast or axilla). Secondary end points included safety and event-free survival (EFS).
Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Combining anti-angiogenesis with chemotherapy yielded increased response rates in patients with early-stage human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This phase II study aims to evaluate the efficacy and safety of adding anlotinib to standard neoadjuvant chemotherapy in primary (HER2)-negative breast cancer.
Patients aged 18 years or older with previously untreated stage Ⅱ-III histologically documented (HER2)-negative breast cancer were assigned to receive chemotherapy plus oral Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles). Chemotherapy comprised of pirarubicin at 50 mg/m2 and cyclophosphamide at 500 mg/m2 and albumin-bound paclitaxel at 200 mg/m2, (d1, 21 days per cycle; both total 6 cycles), which was then followed by surgery. The primary endpoint was pathologic complete response (pCR) (no invasive carcinoma in breast or axilla). Secondary end points included safety and event-free survival (EFS). Stratification was based on the clinical breast cancer stage .
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Anlotinib | Experimental | Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anlotinib | Drug | Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles: albumin-bound paclitaxel (200mg/m2, 1d Q3W) + pirarubicin （50mg/m2, 1d Q3W) + cyclophosphamide (500mg/m2, 1d Q3W); |
| Measure | Description | Time Frame |
|---|---|---|
| Pathological Complete Response (pCR) Rate | Pathological complete response (pCR),which was also identified as total pCR (tpCR), was defined as the absence of invasive cancer in breast and no metastasis to regional lymph nodes (ypT0/is ypN0) in the surgical specimen after completion of neoadjuvant therapy, corresponding to Residual Cancer Burden (RCB) score of 0. Pathological response was evaluated by an independent pathologist blinded to treatment assignment on the resected breast specimen and axillary lymph nodes using H&E staining. The RCB grading system was used as the primary method to quantify residual disease. RCB I indicates minimal residual disease. RCB II indicates moderate residual disease. RCB III indicates extensive residual disease (worst outcome). Lower RCB scores represent better pathological response and are associated with improved long-term survival outcomes. tpCR was considered the most stringent and clinically meaningful endpoint for neoadjuvant studies, representing complete eradication of invasive tumor. | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
| Measure | Description | Time Frame |
|---|---|---|
| RCB 0/I Rate | The outcome measure is defined as the proportion of participants who achieve a Residual Cancer Burden (RCB) class of 0 or I following neoadjuvant therapy and surgical resection. RCB score is calculated using the standardized RCB calculator. Pathological evaluation is performed on surgical specimens according to institutional or central laboratory guidelines. RCB 0: Pathologic complete response (pCR), defined as no residual invasive carcinoma in the breast primary tumor and ipsilateral axillary lymph nodes (in situ carcinoma allowed). RCB I: Minimal residual tumor burden, indicating extensive tumor regression with only minor residual disease. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ting Wang, PhD | Xijing Hospital Affiliated to Air Force Military Medical University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Xijing Hospital Affiliated to Air Force Military Medical University | Xi'an | Shannxi Province | 710032 | China |
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After providing informed consent, patients underwent baseline assessments including physical examination, breast MRI, core needle biopsy for histological confirmation, and immunohistochemistry staining for ER, PR, HER2, and Ki-67. Eligibility was confirmed based on theinclusion and exclusion criteria. Patients who met all inclusion criteria and none of the exclusion criteria were enrolled and assigned to receive study treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Anlotinib | Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles. Anlotinib: Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles: albumin-bound paclitaxel (200mg/m2, 1d Q3W) + pirarubicin （50mg/m2, 1d Q3W) + cyclophosphamide (500mg/m2, 1d Q3W); |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Anlotinib | Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles. Anlotinib: Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles: albumin-bound paclitaxel (200mg/m2, 1d Q3W) + pirarubicin （50mg/m2, 1d Q3W) + cyclophosphamide (500mg/m2, 1d Q3W); |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median age, years (range) |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Pathological Complete Response (pCR) Rate | Pathological complete response (pCR),which was also identified as total pCR (tpCR), was defined as the absence of invasive cancer in breast and no metastasis to regional lymph nodes (ypT0/is ypN0) in the surgical specimen after completion of neoadjuvant therapy, corresponding to Residual Cancer Burden (RCB) score of 0. Pathological response was evaluated by an independent pathologist blinded to treatment assignment on the resected breast specimen and axillary lymph nodes using H&E staining. The RCB grading system was used as the primary method to quantify residual disease. RCB I indicates minimal residual disease. RCB II indicates moderate residual disease. RCB III indicates extensive residual disease (worst outcome). Lower RCB scores represent better pathological response and are associated with improved long-term survival outcomes. tpCR was considered the most stringent and clinically meaningful endpoint for neoadjuvant studies, representing complete eradication of invasive tumor. | Per-protocol set (PPS): patients who completed 6 cycles of neoadjuvant anlotinib plus nab-P-EC, underwent radical surgery, and had evaluable pathological specimens | Posted | Count of Participants | Participants | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
From first dose of study treatment through completion of neoadjuvant therapy and postoperative assessment, up to approximately 24-30 weeks per participant
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Anlotinib | Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that strongly inhibits VEGFR, PDGFR, FGFR, and c-kit. Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles. Anlotinib: Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles) Combined TAC×6 cycles: albumin-bound paclitaxel (200mg/m2, 1d Q3W) + pirarubicin （50mg/m2, 1d Q3W) + cyclophosphamide (500mg/m2, 1d Q3W); |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alopecia | Skin and subcutaneous tissue disorders | Systematic Assessment |
The inherent single-arm, non-randomized design and the limited sample size affect the reliability of efficacy
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ting Wang | Department of Thyroid, Breast, and Vascular Surgery, Xijing Hospital, the Fourth Military Medical University | +86 029 84775271 | ting_w100@126.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 2, 2021 | Apr 11, 2026 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 2, 2021 | Apr 11, 2026 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| C000625192 | anlotinib |
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Assigned to receive chemotherapy plus oral Anlotinib (12 mg qd, d1-14; 21 days per cycle; total 5 cycles)，chemotherapy comprised of pirarubicin at 50 mg/m2 and cyclophosphamide at 500 mg/m2 and albumin-bound paclitaxel at 200 mg/m2, (d1, 21 days per cycle; both total 6 cycles), which was then followed by surgery.
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Check all roles that are masked or check None.
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| At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
| Number of Participants With Treatment-Related Adverse Events (TRAEs) | For safety evaluation, the severity grade (according to National Cancer Institute Common Terminology Criteria for Adverse Events, v 5.0) and the relationship to study treatment of AEs were assessed by physical examination and laboratory tests before and after every cycle, during follow-up visits, and upon indication by symptoms. | From first dose of study treatment through completion of neoadjuvant therapy and postoperative assessment, up to approximately 24-30 weeks per participant |
| EFS | EFS(Event-free survival) | Long-term follow-up schedule for disease status and survival entailed evaluations every 3 months in the first 2 years after surgery, every 6 months for the subsequent three years, and then annually thereafter until the 10th year. |
| bpCR Rate | The outcome measure is defined as the proportion of participants who achieve breast pathologic complete response (bpCR) following neoadjuvant therapy and surgical resection. bpCR is defined as no residual invasive carcinoma in the breast primary tumor (residual ductal carcinoma in situ [DCIS] is allowed), regardless of axillary lymph node status. | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
| apCR Rate | The outcome measure is defined as the proportion of participants who achieve axillary pathologic complete response (apCR) following neoadjuvant therapy and surgical resection. apCR is defined as no residual invasive carcinoma in the ipsilateral axillary lymph nodes, regardless of breast primary tumor status. | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
| Median |
| Full Range |
| years |
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| Sex: Female, Male | the sex of patients | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Tumor size (T stage) | T stage was determined according to the American Joint Committee on Cancer (AJCC) 8th edition staging system for breast cancer, based on physical examination, breast ultrasound, and breast MRI. T1 indicates tumor size ≤2 cm. T2 indicates tumor size >2 cm but ≤5 cm. T3 indicates tumor size >5 cm. T4 indicates direct extension to chest wall or skin. Higher T stages represent larger or more locally invasive tumors and worse outcomes. | Count of Participants | Participants |
|
| Lymph Node Status (N stage) | N stage was assessed according to the American Joint Committee on Cancer (AJCC) 8th edition staging system, based on biopsy, ultrasound and MRI. N0 indicates no regional lymph nodes (LNs) metastasis. N1 indicates metastasis of 1-3 ipsilateral axillary LNs. N2 indicates metastasis of 4-9 ipsilateral axillary LNs or clinically apparent internal mammary LN metastasis without axillary involvement. N3 indicates metastasis to ≥10 ipsilateral axillary LNs or infraclavicular/supraclavicular/internal mammary LN involvement. Higher N stages represent more lymph node involvement and worse outcomes. | Count of Participants | Participants |
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| Secondary | RCB 0/I Rate | The outcome measure is defined as the proportion of participants who achieve a Residual Cancer Burden (RCB) class of 0 or I following neoadjuvant therapy and surgical resection. RCB score is calculated using the standardized RCB calculator. Pathological evaluation is performed on surgical specimens according to institutional or central laboratory guidelines. RCB 0: Pathologic complete response (pCR), defined as no residual invasive carcinoma in the breast primary tumor and ipsilateral axillary lymph nodes (in situ carcinoma allowed). RCB I: Minimal residual tumor burden, indicating extensive tumor regression with only minor residual disease. | Per-protocol set (PPS): patients who completed 6 cycles of neoadjuvant anlotinib plus nab-P-EC, underwent radical surgery, and had evaluable pathological specimens. | Posted | Count of Participants | Participants | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
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| Secondary | Number of Participants With Treatment-Related Adverse Events (TRAEs) | For safety evaluation, the severity grade (according to National Cancer Institute Common Terminology Criteria for Adverse Events, v 5.0) and the relationship to study treatment of AEs were assessed by physical examination and laboratory tests before and after every cycle, during follow-up visits, and upon indication by symptoms. | Posted | Number | participants | From first dose of study treatment through completion of neoadjuvant therapy and postoperative assessment, up to approximately 24-30 weeks per participant |
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| Secondary | EFS | EFS(Event-free survival) | Not Posted | Feb 2034 | Long-term follow-up schedule for disease status and survival entailed evaluations every 3 months in the first 2 years after surgery, every 6 months for the subsequent three years, and then annually thereafter until the 10th year. | Participants |
| Secondary | bpCR Rate | The outcome measure is defined as the proportion of participants who achieve breast pathologic complete response (bpCR) following neoadjuvant therapy and surgical resection. bpCR is defined as no residual invasive carcinoma in the breast primary tumor (residual ductal carcinoma in situ [DCIS] is allowed), regardless of axillary lymph node status. | Per-protocol set (PPS): patients who completed 6 cycles of neoadjuvant anlotinib plus nab-P-EC, underwent radical surgery, and had evaluable pathological specimens. | Posted | Count of Participants | Participants | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
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| Secondary | apCR Rate | The outcome measure is defined as the proportion of participants who achieve axillary pathologic complete response (apCR) following neoadjuvant therapy and surgical resection. apCR is defined as no residual invasive carcinoma in the ipsilateral axillary lymph nodes, regardless of breast primary tumor status. | Per-protocol set (PPS): patients who completed 6 cycles of neoadjuvant anlotinib plus nab-P-EC, underwent radical surgery, and had evaluable pathological specimens. | Posted | Count of Participants | Participants | At definitive surgery, performed after completion of 6 cycles of neoadjuvant systemic therapy (approximately 18-24 weeks from treatment initiation). |
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| 0 |
| 31 |
| 0 |
| 31 |
| 31 |
| 31 |
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment |
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| Nausea/vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Oral Mucositis | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Fatigue | General disorders | Systematic Assessment |
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| AST/ALT increased | Hepatobiliary disorders | Systematic Assessment |
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| Paresthesia | Nervous system disorders | Systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
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| Blood bilirubin increased | Hepatobiliary disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
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| Aneima | Blood and lymphatic system disorders | Systematic Assessment |
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| Hypertension | Vascular disorders | Systematic Assessment |
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| Hand-foot syndrome | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Proteinuria | Renal and urinary disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Oral Mucosal hemorrhage | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Rhinorrhagia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Hypothyroidism | Endocrine disorders | Systematic Assessment |
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| D017437 |
| Skin and Connective Tissue Diseases |