ctDNA-Guided De-Escalation of Adjuvant Chemotherapy With Dalpiciclib in HR-Positive/HER2-Negative Breast Cancer

NCT06970912 | Recruiting Phase 2

• 1 other identifier: MA-BC-Ⅱ-100
• Study Type: interventional
• Target: 393
• Locations: 1 country
• Sites: 1

Brief 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 ：
• 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:
• Primary Goals ： Assess ctDNA clearance rate (conversion from detectable to undetectable ctDNA) after neoadjuvant therapy in Group B.
• 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.

Conditions

Hormone Receptor-Positive Breast Cancer; High-risk Breast Cancer; Early-Stage Breast Cancer; HER2-negative Breast Cancer; ctDNA Monitoring; Breast Cancer Early Stage Breast Cancer (Stage 1-3)

Keywords

HR-positive HER2-negative breast cancer; Early-stage breast cancer; Dalpiciclib; CDK4/6 inhibitor; ctDNA-guided therapy; Adjuvant chemotherapy de-escalation; Circulating tumor DNA (ctDNA); Event-free survival (EFS); Chemotherapy sparing; Personalized therapy; Biomarker-guided therapy

Outcome Measures

Primary Outcomes (2)

• ctDNA Clearance Rate after Neoadjuvant Therapy

  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.

  From baseline to 4 weeks post-neoadjuvant therapy (pre-surgery)

• 3-Year Event-Free Survival (EFS)

  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.

  From randomization to 36 months post-surgery

Secondary Outcomes (5)

• 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

Study Arms (2)

Taxane Neoadjuvant Chemo ± Adjuvant Therapy

ACTIVE COMPARATOR

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.

Drug: Taxane-Based Neoadjuvant Chemotherapy

Dalpiciclib + AI with ctDNA-Driven Adjuvant

EXPERIMENTAL

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: 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: Adjuvant chemotherapy → dalpiciclib + ET for 2 years. Premenopausal women receive ovarian suppression with LHRH agonists.

Drug: Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy

Interventions

Dalpiciclib + Aromatase Inhibitor with ctDNA-Guided Therapy DRUG

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.

Also known as: Dalpiciclib/AI combination therapy, SHR6390 + aromatase inhibitor

Dalpiciclib + AI with ctDNA-Driven Adjuvant

Taxane-Based Neoadjuvant Chemotherapy DRUG

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.

Also known as: Paclitaxel/cyclophosphamide neoadjuvant therapy, Docetaxel-based chemotherapy regimen

Taxane Neoadjuvant Chemo ± Adjuvant Therapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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);

You may not qualify if:

• 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;

Sponsors & Collaborators

• Peking University People's Hospital: lead

Study Sites (1)

Peking University People's Hospital

Beijing, Beijing Municipality, 100044, China

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

dalpiciclib; Aromatase Inhibitors; Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• shu wang, doctor

  Peking University People's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

yuan peng, doctor

CONTACT

86+13671287670; 13671287670@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: director of breast center

Study Record Dates

• First Submitted: May 6, 2025
• First Posted: May 14, 2025
• Study Start: August 1, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: January 21, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)