ctDNA-Guided De-Escalation of Adjuvant Chemotherapy With Dalpiciclib in HR-Positive/HER2-Negative Breast Cancer
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
Peking University People's Hospital
393 participants
Aug 1, 2025
INTERVENTIONAL
Conditions
Summary
* 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 ： 1. 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). 2. 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.
Eligibility
Inclusion Criteria19
- 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-3N0M0 with high-risk factors (Grade 3, or Grade 2 with Ki67 ≥20%);
- Any TN+M0;
- 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.
Exclusion Criteria16
- 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.
Interventions
Patients receive 4 cycles of neoadjuvant dalpiciclib (125 mg orally, days 1-21 of 28-day cycles) combined with an aromatase inhibitor (letrozole/anastrozole/exemestane). Post-surgery treatment is guided by ctDNA status: （1）ctDNA-negative at baseline and post-neoadjuvant, with post-op Ki67 ≤10% :Continue dalpiciclib + endocrine therapy (ET) for 2 years； （2）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；（3）Persistently ctDNA-positive or ctDNA-negative → positive: Mandatory adjuvant chemotherapy → dalpiciclib + ET for 2 years. Premenopausal women undergo ovarian suppression with LHRH agonists.
Patients receive 4 cycles of taxane-based neoadjuvant chemotherapy (e.g., paclitaxel 80 mg/m² weekly or docetaxel 75-100 mg/m² triweekly) before surgery. Post-surgery adjuvant chemotherapy (physician's choice) may be administered. This arm serves as the control group for comparing standard chemotherapy efficacy.
Locations(1)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT06970912