Neoadjuvant SBRT Followed by Nab-Paclitaxel Combined With Toripalimab in HR+/HER2- Breast Cancer: A Single-arm, Prospective Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 27
- 试验地点
- 2
- 主要终点
- Pathologic complete response (pCR) rate according to RCB system
研究概览
简要总结
The goal of this clinical trial is to evaluate the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) followed by nab-paclitaxel combined with toripalimab in patients with previously untreated HR+/HER2-negative breast cancer. Eligible patients include those with stage IIB-IIIC disease (cT3N0, cT2-4N1-3 or cT1N2-3) or stage IIA disease (cT2N0 or cT1N1) with at least two of the following high-risk factors: histologic grade 3, Ki-67 ≥50% or premenopausal with age <50 years. A total of 27 enrolled patients will be assigned to receive the combination therapy. The primary question it aims to answer is whether this combination of radiotherapy, de-escalated chemotherapy, and immunotherapy can improve the total pathologic complete response (tpCR) rate (defined as ypT0/Tis ypN0).
详细描述
HR-positive and HER2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer. Although this subtype is generally associated with favorable overall survival, patients with high-risk features remain at substantial risk for late recurrence and distant metastasis. In particular, those presenting with large primary tumors (cT3 or higher) or axillary lymph node involvement face a significantly elevated risk of locoregional recurrence and distant metastasis relative to patients with earlier-stage, lower-risk disease.
In recent years, the role of neoadjuvant therapy in the comprehensive treatment of breast cancer has gained increasing attention. The pathological complete response (pCR) rate following neoadjuvant therapy is closely associated with long-term survival. However, compared to HER2+ or triple-negative breast cancer, HR+/HER2- breast cancer patients exhibit a significantly lower pCR rate with neoadjuvant chemotherapy alone. Neoadjuvant chemotherapy combined with immunotherapy has become a key treatment strategy for TNBC, this combination also improves pCR rates in HR+/HER2- breast cancer, though the benefit is less pronounced than in TNBC. Radiotherapy not only releases a large number of tumor antigens and inflammatory signals to enhance systemic anti-tumor immune responses, but also promotes the exposure of tumor cell surface antigens, thereby increasing the immunogenicity of the tumor microenvironment. The synergistic effect of radiotherapy and immunotherapy, when combined with chemotherapy, may further improve treatment efficacy. Based on these, we designed this clinical trial evaluating the effect of neoadjuvant radiotherapy combined with de-escalated chemotherapy and immunotherapy, aiming to explore its potential to improve pCR rates and long-term outcomes in HR+/HER2- breast cancer patients. Enrolled patients will receive four cycles of single-agent Nab-Paclitaxel plus Toripalimab within one week after stereotactic radiotherapy, followed by surgery and subsequent adjuvant therapy. Postoperative pCR rate and prognosis of participants will be analyzed in our clinical study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female patients aged ≥18 and ≤75 years at the time of signing informed consent.
- •ECOG PS status of 0-
- •Histologically confirmed non-metastatic (M0) breast cancer, meeting all of the following:
- •a) Clinical stage (per AJCC 8th edition) meeting one of the following: i. cT3N0, cT2-4N1-3, or cT1N2-3 (Stage IIB, IIIA, IIIB, or IIIC); ii. cT2N0 or cT1N1 (Stage IIA) with at least two of the following high-risk features: Histologic grade 3; Ki-67 ≥50%; Age <50 years and premenopausal status.
- •b) Imaging assessments within 28 days prior to enrollment including: abdominal CT or ultrasound, bone scan (ECT), chest CT, and brain MRI.
- •Histologically or pathologically confirmed invasive carcinoma, with all of the following:
- •Grade 2 or 3 (confirmed by central laboratory);
- •ER-positive (>1% staining) and/or PR-positive (>1% staining) by IHC;
- •HER2-negative (IHC 0/1+ or HER2/neu FISH ratio ≤1.8);
- •Ki-67 ≥15%.
- •Patient deemed eligible for radiotherapy after MDT evaluation.
- •No prior antitumor therapy within 1 month before enrollment.
- •Organ Function Requirements (within 7 days prior to enrollment):
- •Complete blood count (no transfusion or hematopoietic growth factors within 7 days): ANC ≥1.5×10⁹/L; ALC ≥0.5×10⁹/L; Platelets ≥100×10⁹/L; Hemoglobin ≥90 g/L; WBC ≥3.0×10⁹/L and ≤15×10⁹/L;
- •Blood biochemistry (no transfusion/albumin within 7 days): ALT/AST ≤2.5×ULN; ALP ≤2.5×ULN；BUN/Cr ≤1.5×ULN; Cr≥60 mL/min (Cockcroft-Gault formula);
- •Coagulation: PT/APTT ≤1.5×ULN; INR ≤1.5×ULN (if no anticoagulant therapy);
- •Urinalysis: Urine protein <2+; if ≥2+, 24-hour urine protein must be ≤1g;
- •Thyroid function:TSH ≤1×ULN; if abnormal, normal T3/T4 levels required for eligibility.
- •Women of childbearing potential must:
- •Have a negative serum pregnancy test within 7 days before treatment;
- •Use highly effective contraception during the study and for 180 days after the last dose.
- •Voluntarily sign informed consent, demonstrate good compliance, and commit to follow-up.
排除标准
- •Inflammatory Breast Cancer.
- •Comorbidities/Medical History:
- •Autoimmune disease: patients with any known or suspected autoimmune disease, except: hypothyroidism due to autoimmune thyroiditis managed with hormone replacement therapy only, stable type-1 diabetes with well-controlled blood glucose.
- •Cardiovascular Diseases: poorly controlled hypertension despite medication (SBP >140 mmHg or DBP>90 mmHg). And with the history (within 6 months prior to enrollment) of myocardial infarction, severe/unstable angina, NYHA Class ≥2 heart failure, clinically significant arrhythmias as well as symptomatic congestive heart failure.
- •Interstitial lung disease, non-infectious pneumonitis, or other uncontrolled systemic diseases (e.g., diabetes, pulmonary fibrosis, acute pneumonia);
- •Vaccination: receipt of live attenuated vaccines within 28 days prior to enrollment or planned during the study;
- •Infections: HIV/AIDS, active hepatitis(HBV-DNA ≥500 IU/mL; HCV-RNA above detection limit), or co-infection with HBV and HCV, severe infections within 4 weeks prior to enrollment (e.g., bacteremia, severe pneumonia requiring hospitalization), active infection requiring systemic antibiotics (CTCAE≥Grade 2) within 2 weeks prior to treatment, active tuberculosis within 1 year prior to enrollment;
- •Unexplained fever >38.5°C during screening (unless deemed tumor-related by the investigator);
- •Malignancy History: other malignancies diagnosed within 5 years prior to enrollment (except adequately treated basal cell carcinoma, squamous cell skin cancer, or cervical carcinoma in situ);
- •Surgery:Major surgery within 28 days prior to enrollment (diagnostic biopsies or PICC line placement are allowed);
- •Transplant: Prior or planned allogeneic bone marrow or solid organ transplant;
- •Neurological: peripheral neuropathy ≥Grade 2;
- •Gastrointestinal: clinically significant bowel obstruction;
- •Thrombotic Events: arterial/venous thrombosis within 6 months prior to enrollment (e.g., stroke, transient ischemic attack, DVT, pulmonary embolism);
- •Bleeding Risk: hemoptysis (≥2.5 mL/day) within 2 months prior to enrollment, clinically significant bleeding within 3 months prior to enrollment (e.g. gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood≥++), and the known bleeding/thrombotic disorders (e.g., hemophilia, coagulopathy, thrombocytopenia, hypersplenism);
- •Coagulation abnormalities (INR >1.5×ULN or APTT >1.5×ULN), or requiring long-term anticoagulation (warfarin/heparin) or antiplatelet therapy (aspirin≥300 mg/day or clopidogrel ≥75 mg/day).
- •Treatment-Related Exclusions:
- •Prior systemic targeted therapy or immunostimulants (e.g., interferon, IL-2) within 4 weeks before treatment;
- •Known allergy to the investigational drug (recombinant humanized anti-PD-1 mAb) or its excipients.
- •Clinical Trial Participation: participation in another drug trial within 4 weeks prior to enrollment, or within 5 half-lives of the last investigational drug dose.
- •Substance Abuse: history of drug/alcohol abuse or dependency.
- •Pregnancy/Lactation: pregnant, breastfeeding, or planning pregnancy during the study.
- •Investigator' s Discretion: other conditions that may compromise subject safety or study integrity (e.g., severe lab abnormalities, social factors).
研究组 & 干预措施
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Neoadjuvant Chemotherapy (Drug)
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Stereotactic Body Radiation Therapy (SBRT) (Radiation)
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Surgery (Procedure)
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Adjuvant Chemotherapy (Drug)
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Adjuvant Radiotherapy (Radiation)
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Endocrine therapy (Drug)
Treatment
During the neoadjuvant treatment period, participants will undergo stereotactic radiotherapy and subsequently receive chemotherapy combined with immunotherapy.
干预措施: Toripalimab (Drug)
结局指标
主要结局
Pathologic complete response (pCR) rate according to RCB system
时间窗: Up to 12 months
pCR is defined as the absence of invasive cancer in the breast primary lesion and negative regional lymph nodes (ypT0/Tis ypN0) by hematoxylin-eosin staining after completion of the neoadjuvant treatment. RCB system will be used for the pathological evaluation after neoadjuvant therapy
Total pathologic complete response (tpCR) rate according to RCB system
时间窗: At definitive surgery, following completion of neoadjuvant SBRT and 4 cycles of nab-paclitaxel plus toripalimab (each cycle is 21 days), approximately 4 months from start of neoadjuvant therapy.
tpCR is defined as the absence of invasive carcinoma in the breast primary lesion and negative regional lymph nodes (ypT0/Tis ypN0) by hematoxylin-eosin staining after completion of the neoadjuvant treatment. RCB system will be used for the pathological evaluation after neoadjuvant therapy
次要结局
- RCB 0/I rate(Up to 12 months)
- DFS and iDFS(1 year, 2 year, 3 year and 5 year)
- RCB 0/I rate(At definitive surgery, following completion of neoadjuvant SBRT and 4 cycles of nab-paclitaxel plus toripalimab (each cycle is 21 days), approximately 4 months from start of neoadjuvant therapy.)
- Breast pathologic complete response (bpCR) rate(At definitive surgery, following completion of neoadjuvant SBRT and 4 cycles of nab-paclitaxel plus toripalimab (each cycle is 21 days), approximately 4 months from start of neoadjuvant therapy.)
- Axillary pathologic complete response (apCR) rate(At definitive surgery, following completion of neoadjuvant SBRT and 4 cycles of nab-paclitaxel plus toripalimab (each cycle is 21 days), approximately 4 months from start of neoadjuvant therapy.)
- Objective response rate (ORR)(From start of neoadjuvant therapy until definitive surgery, assessed every 2 cycles (each cycle is 21 days) during neoadjuvant treatment.)
- EFS(From date of first neoadjuvant treatment until the date of first documented event, assessed up to 5 years.)
- iDFS(From date of first neoadjuvant treatment until the date of first documented invasive disease recurrence or death, assessed up to 5 years.)
- OS(From date of first neoadjuvant treatment until the date of death from any cause, assessed up to 5 years.)
- Safety and tolerability(From signing of informed consent through 30 days after the last dose of study treatment, assessed up to 5 years.)