A Prospective, Multicenter, Randomized, Open-Label Phase II Study of ctDNA-Guided De-Escalation of Adjuvant Chemotherapy With Dalpiciclib in HR-Positive/HER2-Negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 393
- 试验地点
- 1
- 主要终点
- ctDNA Clearance Rate after Neoadjuvant Therapy
研究概览
简要总结
- This is a Phase II, multicenter, randomized clinical trial evaluating a ctDNA-guided approach to de-escalate adjuvant chemotherapy in patients with hormone receptor (HR)-positive, HER2-negative early-stage breast cancer. The study aims to determine if combining the CDK4/6 inhibitor Dalpiciclib with endocrine therapy can reduce the need for chemotherapy while maintaining clinical benefits.
- Key Details ：
- Participants: 393 women (aged 18-75) with early-stage HR+/HER2- breast cancer at high risk of recurrence (e.g., tumor size ≥2 cm, lymph node involvement, or high-grade tumors).
- Design: Patients are randomized 1:4 to two groups:
Group A (Chemotherapy) : Receives 4 cycles of taxane-based chemotherapy before surgery.
Group B (Experimental) : Receives Dalpiciclib + aromatase inhibitor (AI) for 4 cycles pre-surgery.
Post-surgery, treatment is adjusted based on ctDNA results. 3. Primary Goals ： Assess ctDNA clearance rate (conversion from detectable to undetectable ctDNA) after neoadjuvant therapy in Group B.
Evaluate 3-year event-free survival (EFS) in Group B (e.g., freedom from cancer recurrence, progression, or death).
Secondary Goals ： Safety of Dalpiciclib + endocrine therapy. Tumor response rates (e.g., complete cell cycle arrest, pathological remission).
Correlation between ctDNA clearance and long-term outcomes.
- Why This Matters ： Current guidelines recommend chemotherapy for high-risk HR+ breast cancer, but it often causes significant side effects. This study explores a personalized approach using ctDNA-a blood-based biomarker-to identify patients who may safely avoid chemotherapy without compromising survival. If successful, it could shift clinical practice toward less toxic, targeted therapies for eligible patients.
详细描述
- 1. Scientific Background and Rationale： Breast cancer remains a leading cause of cancer-related morbidity and mortality globally, with hormone receptor-positive (HR+), HER2-negative (HER2-) subtypes accounting for approximately 70% of cases. While adjuvant chemotherapy is standard for high-risk early-stage HR+/HER2- breast cancer, it carries significant toxicity, and many patients may not derive clinical benefit. Emerging evidence suggests that circulating tumor DNA (ctDNA)-a minimally invasive biomarker reflecting residual disease-may guide personalized treatment de-escalation.
Preclinical and clinical studies demonstrate that ctDNA dynamics correlate with tumor burden and prognosis. In HR+ breast cancer, ctDNA clearance after neoadjuvant therapy is associated with improved survival, while persistent ctDNA post-treatment predicts recurrence. CDK4/6 inhibitors, such as Dalpiciclib, have revolutionized advanced HR+/HER2- breast cancer management by enhancing endocrine therapy efficacy. However, their role in early-stage disease, particularly in a ctDNA-guided de-escalation strategy, remains underexplored. This study addresses this gap by evaluating whether ctDNA-driven decision-making can safely reduce chemotherapy use while maintaining clinical outcomes.
- 2. Study Objectives
- Primary Objectives
Group B (Experimental Arm):
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open-label study due to the distinct administration routes and side effect profiles of the interventions: Group A receives intravenous taxane-based chemotherapy, while Group B receives oral dalpiciclib combined with aromatase inhibitors. Blinding participants or investigators was not feasible. However, outcome assessors (e.g., central pathology reviewers for residual cancer burden) and ctDNA analysis laboratory personnel were blinded to treatment allocation to minimize bias.
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 breast cancer patients aged ≥18 years and ≤75 years, either postmenopausal or premenopausal/perimenopausal;
- •Pathologically confirmed hormone receptor-positive (HR+), HER2-negative invasive breast cancer:
- •ER-positive and/or PR-positive defined as: ≥10% of tumor cells showing positive staining;
- •HER2-negative defined as: standard immunohistochemistry (IHC) result of 0/1+; or IHC 2+ with negative in situ hybridization (ISH) (confirmed by the central pathology laboratory);
- •At least one evaluable lesion per RECIST 1.1, with clinical staging meeting:
- •T1c-2N0M0 with high-risk factors (Grade 3, or Grade 2 with Ki67 ≥20%);
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;
- •Willing to participate in the study and voluntarily sign informed consent;
- •Agree to undergo ctDNA testing during treatment;
- •Adequate organ and bone marrow function defined as:
- •Absolute neutrophil count (ANC) ≥1,500/mm³ (1.5 × 10⁹/L) (without granulocyte colony-stimulating factor [G-CSF] treatment within 14 days);
- •Platelet count (PLT) ≥100,000/mm³ (100 × 10⁹/L) (without corrective therapy within 7 days);
- •Hemoglobin (Hb) ≥9 g/dL (90 g/L) (without corrective therapy within 7 days);
- •Serum creatinine ≤1.5× upper limit of normal (ULN) or creatinine clearance ≥60 mL/min (without corrective therapy within 7 days);
- •Total bilirubin (TBIL) ≤1.5×ULN (without corrective therapy within 7 days);
- •Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤1.5×ULN (without corrective therapy within 7 days);
- •Cardiac function: left ventricular ejection fraction (LVEF) ≥55%; QTc interval corrected by Fridericia's formula (QTcF) <470 msec on 12-lead ECG;
- •Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization and agree to use non-hormonal contraception from informed consent signing until 2 months after the last treatment.
排除标准
- •HER2-positive breast cancer confirmed by current pathological diagnosis;
- •Inflammatory breast cancer;
- •Stage IV (metastatic) breast cancer;
- •Bilateral breast cancer;
- •Prior history of breast cancer (including ductal carcinoma in situ or invasive breast cancer);
- •Any prior antitumor therapy for the current breast cancer, including systemic therapies (endocrine, chemotherapy, immunotherapy, biological therapy) or local therapies (radiotherapy, vascular embolization, axillary lymph node biopsy);
- •Diagnosis of any malignancy within 5 years prior to randomization, except cured cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin;
- •History of severe pulmonary diseases (e.g., interstitial pneumonia);
- •HIV infection, acquired immunodeficiency syndrome (AIDS), active hepatitis B (HBV DNA ≥500 IU/mL), hepatitis C (HCV antibody-positive with HCV RNA above the lower limit of detection), or co-infection with HBV and HCV;
- •Within 6 months prior to randomization: myocardial infarction, severe/unstable angina, NYHA Class ≥II heart failure, ≥Grade 2 persistent arrhythmia (per NCI CTCAE v5.0), atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident (including transient ischemic attack), or symptomatic pulmonary embolism;
- •Severe active infection within 4 weeks prior to randomization (requiring intravenous antibiotics, antifungals, or antivirals) or unexplained fever >38.5°C during screening/before first dose;
- •Known allergy to any component of the study drugs;
- •Current participation in another interventional drug clinical study;
- •Pregnancy or lactation;
- •Refusal to comply with follow-up;
- •Other severe physical/mental illnesses or laboratory abnormalities that may increase study risk, interfere with results, or render the patient unsuitable per investigator judgment.
研究组 & 干预措施
Taxane Neoadjuvant Chemo ± Adjuvant Therapy
Arm Description:
This group receives neoadjuvant taxane-based chemotherapy (e.g., paclitaxel 80 mg/m² weekly or docetaxel 75-100 mg/m² triweekly for 4 cycles) before surgery. Post-surgery adjuvant chemotherapy (whether or not and how to adopt depend on the physician's choice) may be administered ± CDK4/6 inhibitors. The intervention aims to compare standard chemotherapy efficacy as a control.
Intervention phases:
- Neoadjuvant: Chemotherapy only
- Adjuvant: Optional chemotherapy based on physician discretion ± （CDK4/6 inhibitors+endocrine therapy） Key endpoints: Pathological response 0/1 (RCB 0/1), safety profiles.
干预措施: Taxane-Based Neoadjuvant Chemotherapy (Drug)
Dalpiciclib + AI with ctDNA-Driven Adjuvant
Arm Description:
Patients receive 4 cycles of neoadjuvant dalpiciclib (125 mg/day, 21 days on/7-off) combined with aromatase inhibitors (letrozole/anastrozole/exemestane). Post-surgery treatment is guided by ctDNA status:
- ctDNA-negative at baseline and post-neoadjuvant, with post-op Ki67 ≤10% ：Continue dalpiciclib + endocrine therapy (ET) for 2 years.
- ctDNA-positive → negative, or persistently ctDNA-negative with post-op Ki67 >10% :
Randomized 1:1 to:
- Arm B1: Dalpiciclib + ET for 2 years.
- Arm B2: Adjuvant chemotherapy (investigator's choice) → dalpiciclib + ET for 2 years.
- Persistently ctDNA-positive or ctDNA-negative → positive:
Adjuvant chemotherapy → dalpiciclib + ET for 2 years.
Premenopausal women receive ovarian suppression with LHRH agonists.
干预措施: Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy (Drug)
结局指标
主要结局
ctDNA Clearance Rate after Neoadjuvant Therapy
时间窗: From baseline to 4 weeks post-neoadjuvant therapy (pre-surgery)
Proportion of patients in Group B achieving conversion from detectable to undetectable ctDNA in plasma after 4 cycles of neoadjuvant Dalpiciclib + aromatase inhibitor. ctDNA analysis uses tumor-informed personalized panels (tracking 16 clonal variants via whole-exome sequencing), with clearance defined as ≥2 consecutive negative results at 1% variant allele frequency threshold.
3-Year Event-Free Survival (EFS)
时间窗: From randomization to 36 months post-surgery
Time from randomization to first occurrence of locoregional/distant recurrence, contralateral breast cancer, secondary malignancy, or death from any cause. Assessed via imaging (CT/MRI), pathology, and clinical exams every 3 months for 3 years. Events are adjudicated by blinded independent review committee.
次要结局
- Incidence of Grade ≥3 Treatment-Related Adverse Events (TRAEs)(From first dose to 30 days after last treatment (up to 26 months))
- Residual Cancer Burden (RCB) 0-1 Rate(At surgery (approximately 16 weeks after randomization))
- Complete Cell Cycle Arrest (CCCA) Rate (Ki67 ≤2.7%)(Post-neoadjuvant therapy (pre-surgery, week 16))
- Objective Response Rate (ORR) by RECIST 1.1(Baseline to pre-surgery (week 16))
- Correlation Between ctDNA Clearance and 3-Year EFS(From baseline to 36 months post-surgery)
研究者
Shu Wang
director of breast center
Peking University People's Hospital