HR+/HER2+ Early Breast Cancer
Conditions
Brief summary
This prospective, response-adapted phase II study evaluates the efficacy and safety of neoadjuvant fovinaciclib in combination with aromatase inhibitors and dual HER2 blockade in patients with HR-positive/HER2-positive early breast cancer. All patients initially receive induction treatment with fovinaciclib plus endocrine therapy and HER2-targeted therapy, followed by early assessment of treatment response after 6 weeks of treatment. Patients demonstrating an adequate response continue the same regimen, whereas those with a suboptimal response are transitioned to standard neoadjuvant chemotherapy combined with HER2-targeted therapy prior to surgery. This adaptive approach aims to optimize treatment selection, improve therapeutic efficacy, and reduce unnecessary chemotherapy exposure.
Detailed description
This is a prospective, response-adapted, phase II study designed to evaluate an individualized neoadjuvant treatment strategy based on fovinaciclib in combination with aromatase inhibitors and dual HER2 blockade in patients with HR-positive/HER2-positive early breast cancer. The study incorporates an adaptive treatment algorithm guided by early on-treatment assessment of tumor response, with the aim of optimizing therapeutic efficacy while minimizing unnecessary chemotherapy exposure. All eligible patients initially receive neoadjuvant treatment with fovinaciclib plus endocrine therapy and HER2-targeted therapy according to the study protocol. Following completion of the predefined initial treatment phase, tumor response is assessed according to protocol-defined evaluation methods. Patients who achieve an adequate response continue the same neoadjuvant regimen to complete the planned course of therapy. In contrast, patients demonstrating a suboptimal response are transitioned to standard neoadjuvant chemotherapy combined with HER2-targeted therapy prior to surgery. Postoperative treatment selection and management are conducted according to protocol-defined principles and investigator assessment. By tailoring treatment intensity according to early response, the study seeks to maximize therapeutic benefit in responsive patients while facilitating timely treatment modification for those less likely to benefit from the initial regimen. Primary and secondary objectives include evaluation of clinical efficacy, safety and tolerability of the response-adapted neoadjuvant strategy, and the feasibility of treatment modification based on early response assessment. Exploratory analyses will investigate potential biomarkers associated with treatment response and resistance, with the goal of informing future individualized treatment approaches.
Interventions
DRUGFovinaciclib
CDK4/6 inhibitor
Letrozole or anastrozole
dual HER2 blockade
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Subjects voluntarily agree to participate in the study, fully understand the study procedures, provide written informed consent (ICF), and are willing and able to comply with all study procedures. Female patients aged ≥18 years and ≤75 years. Histologically confirmed HR-positive (ER \>10%) and HER2-positive (IHC 3+ or IHC 2+/ISH+) early-stage or locally advanced invasive breast cancer. Pathologically staged as stage I-III according to the American Joint Committee on Cancer (AJCC) 8th edition staging system. Premenopausal patients must receive ovarian function suppression. Considered suitable for aromatase inhibitor treatment according to investigator assessment. Presence of evaluable disease according to RECIST version 1.1, including measurable and/or non-measurable lesions. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1. Ability to swallow capsules. Adequate bone marrow and organ function, defined as follows: Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L; Hemoglobin ≥100 g/L (without red blood cell transfusion within 14 days prior to randomization); Platelet count ≥100 × 10\^9/L; Total serum bilirubin ≤1.5 × upper limit of normal (ULN); patients with Gilbert syndrome must have total bilirubin ≤3 × ULN; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN; Serum creatinine \<1.5 × ULN or creatinine clearance ≥50 mL/min; Left ventricular ejection fraction (LVEF) ≥50%; QT interval ≤480 ms.
Exclusion criteria
Current participation in another clinical trial involving investigational therapy, or participation in any other medical study considered scientifically or medically incompatible with this study. Bilateral breast cancer, inflammatory breast cancer, or occult breast cancer. History of uncontrolled seizures or central nervous system disease. History of other malignancies within the past 5 years. Pregnant or breastfeeding women. Known severe hypersensitivity to any component of the study drugs. Severe comorbidities, including uncontrolled hypertension (e.g., systolic blood pressure \>180 mmHg or diastolic blood pressure \>100 mmHg), uncontrolled diabetes mellitus, or active infection. Patients with adequately controlled hypertension may be enrolled. Clinically uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage or medical intervention within 2 weeks prior to first dosing. Myocardial infarction within 6 months prior to first dosing; uncontrolled arrhythmia (QTc ≥470 ms, calculated using Fridericia's formula); New York Heart Association (NYHA) class III-IV heart failure; LVEF \<50%; or clinically significant pleural effusion, pericardial effusion, or ascites requiring intervention. Dysphagia, active gastrointestinal disease, history of major gastrointestinal surgery, malabsorption syndrome, or any condition that may affect absorption of study drugs. Active hepatitis B infection \[HBsAg-positive with detectable HBV-DNA\], active hepatitis C infection \[HCV antibody-positive with detectable HCV-RNA\], positive syphilis screening (except confirmed inactive infection), known HIV infection, or positive HIV screening result. Receipt of major surgery, radiotherapy, tumor immunotherapy, monoclonal antibody-based antitumor therapy, or other systemic antitumor therapies considered by the investigator to interfere with study treatment efficacy within 28 days prior to first dosing. Planned or previous organ transplantation or bone marrow transplantation. Known history of psychiatric substance abuse or drug addiction. Any other condition that, in the investigator's judgment, would make the subject unsuitable for participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Pathological Complete Response (tpCR) Rate: ypT0/Tis, ypN0 | 24 weeks | The tpCR rate is defined as the proportion of participants with no residual invasive cancer cells in both the breast primary tumor site (residual in situ cancer cells are permitted) and all sampled axillary lymph nodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Breast Pathological Complete Response (bpCR) Rate: ypT0/Tis | 24 weeks | The bpCR rate is defined as the proportion of participants with no residual invasive cancer cells in the breast primary tumor site (residual in situ cancer cells are permitted). |
| Objective Response Rate (ORR) | 24 weeks | ORR is defined as the proportion of participants with a complete or partial response. |
| Event-Free Survival (EFS) | Approximately five years | EFS is defined as the time from randomization to any of the following events: precludes surgery, local or distant recurrence, second primary malignancy, or death due to any cause. |
| Adverse Event (AE) | Approximately three years | An AE is defined as any untoward medical occurrence in a study participant administered a medicinal product, temporally associated with study intervention, without presumption of causality. |
| Complete cell cycle arrest (CCCA) | 6 weeks | Ki67≤2.7% |
Countries
China
Contacts
CONTACTYunxiang Zhou
Outcome results
None listed