Breast Cancer
Conditions
Brief summary
This phase II single-arm study is designed to evaluate the neoadjuvant efficacy of a chemotherapy-free regimen consisting of trastuzumab, pertuzumab, Culmerciclib, and fulvestrant in patients with treatment-naïve stage II-III hormone receptor-positive, HER2-positive breast cancer. The pathological complete response (pCR) rate serves as the primary endpoint. The study aims to assess whether the pCR rate meets or exceeds that achieved with standard chemotherapy plus dual HER2-targeted therapy, and to generate preliminary evidence to support the design of a future phase III randomized controlled trial.
Detailed description
Patients with HR-positive/HER2-positive breast cancer have a suboptimal response to neoadjuvant chemotherapy combined with dual HER2 blockade, and an optimal treatment strategy for this population has not been established. Trastuzumab and pertuzumab are monoclonal antibodies that target HER2, while Culmerciclib is a novel CDK2/4/6 inhibitor with enhanced inhibitory activity against CDK2 and CDK4 compared with abemaciclib and palbociclib. Fulvestrant is a selective estrogen receptor downregulator. Concurrent inhibition of HER2, ER, and CDK4/6 pathways may synergistically overcome cross-talk-mediated resistance and improve antitumor efficacy. This study will explore whether the chemotherapy-sparing regimen of trastuzumab plus pertuzumab combined with fulvestrant and Culmerciclib improves pathological response in patients with previously untreated stage II-III HR-positive/HER2-positive early breast cancer. This is a single-arm, open-label, phase II study. Approximately 31 women with stage II-III (T2-4, any N, M0 or any T, N1-3, M0 according to AJCC 8th edition) HR-positive/HER2-positive early or locally advanced breast cancer will be enrolled. Eligible participants must be treatment-naïve with histologically confirmed HER2-positive (IHC 3+ or ISH-positive) and HR-positive (ER-positive and/or PR-positive, ≥1% staining) invasive breast carcinoma. Participants will receive neoadjuvant trastuzumab (loading dose 8 mg/kg, then 6 mg/kg q3w) plus pertuzumab (loading dose 840 mg, then 420 mg q3w) for six cycles, combined with Culmerciclib180 mg orally once daily (28-day cycle) and fulvestrant 500 mg intramuscularly (day 1 and day 15 of cycle 1, then day 1 of each subsequent cycle). Premenopausal and perimenopausal participants will receive ovarian function suppression with LHRH agonists. Surgery will be performed within 3-6 weeks after completion of neoadjuvant treatment. The primary endpoint is total pathological complete response (tpCR; ypT0/Tis, ypN0) assessed by the investigator after surgery. Secondary endpoints include breast pathological complete response (bpCR; ypT0/Tis), objective response rate (ORR) per RECIST 1.1, residual cancer burden (RCB) class, changes in Ki-67 expression from baseline to surgery, and patient-reported outcomes (EORTC QLQ-C30). Safety endpoints include the incidence of adverse events and serious adverse events. Exploratory analyses will assess the correlation between ctDNA dynamics and pCR using peripheral blood and tumor tissue specimens collected at protocol-specified time points.
Interventions
Trastuzumab will be administered intravenously at an initial loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for six cycles. The first infusion will last approximately 90 minutes; if the initial infusion is well tolerated, subsequent infusions may be shortened to 30 minutes. If the interval between two consecutive trastuzumab infusions reaches 6 weeks or longer due to adverse events or other reasons, a re-loading dose of 8 mg/kg should be given over approximately 90 minutes, followed by 6 mg/kg every 3 weeks thereafter, with each infusion lasting 30 minutes, for a total of six cycles.
DRUGPertuzumab
Pertuzumab will be administered intravenously at an initial loading dose of 840 mg over 60 minutes, followed by 420 mg every 3 weeks, with each infusion lasting 30 to 60 minutes, for six cycles. A 30- to 60-minute observation period is recommended after each pertuzumab infusion before proceeding with trastuzumab or chemotherapy. If the interval between two consecutive pertuzumab infusions reaches 6 weeks or longer due to adverse events or other reasons, a re-loading dose of 840 mg should be given over 60 minutes, followed by 420 mg every 3 weeks thereafter, with each infusion lasting 30 to 60 minutes, for a total of six cycles.
DRUGCulmerciclib
Culmerciclib will be administered orally at 180 mg once daily on a continuous schedule in 28-day cycles, taken with meals or within 2 hours after meals. Dosing at a fixed time each day is recommended. If a dose is missed and the next scheduled dose is within 10 hours, the missed dose should not be taken.
DRUGFulvestrant
Fulvestrant will be administered intramuscularly at 500 mg on Day 1 and Day 15 of Cycle 1, and thereafter on Day 1 of each subsequent 28-day cycle.
Sponsors
Hebei Medical University Fourth Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following inclusion criteria to be enrolled in this study： 1. The participant voluntarily joins this study, signs the informed consent form, and has good compliance. 2. Female, aged 18-75 years (at the time of signing the informed consent form), meeting one of the following criteria: 1. Has undergone bilateral oophorectomy, or is aged ≥60 years; 2. Aged \<60 years, with continuous amenorrhea for 12 months without pathological or physiological cause, and postmenopausal levels of estradiol (E2) and follicle-stimulating hormone (FSH); 3. Premenopausal or perimenopausal female, willing to receive luteinizing hormone-releasing hormone (LHRH) agonist therapy during the study. 3. ECOG performance status score: 0-1. 4. Life expectancy \>6 months. 5. Histologically or cytologically confirmed HER2-positive invasive breast carcinoma, with HER2 testing meeting the following requirements: 1. HER2 positivity confirmed or verified by the pathology department of the participating center: according to the 2018 ASCO/CAP HER2 testing guidelines, HER2 positivity is defined as immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive; 2. For multicentric tumors (multiple tumors involving more than one breast quadrant), one lesion must be sampled from each involved quadrant, and all must be confirmed or verified as HER2 positive by the pathology department of the participating center. 6. HR-positive: ER-positive and/or PR-positive (according to the 2020 ASCO/CAP guidelines, HR positivity includes ER-positive and/or PR-positive, defined as positive staining in ≥1% of tumor cells). 7. Clinical stage at presentation: T2-4, any N, M0 OR any T, N1-3, M0 (per AJCC 8th edition breast cancer staging system). 8. The participant agrees to undergo breast cancer resection surgery when surgical criteria are met after neoadjuvant therapy. 9. Adequate major organ function, meeting the following criteria: 1. Hemoglobin (HGB) ≥90 g/L (without blood transfusion or use of hematopoietic stimulating factors within 7 days prior to examination); 2. Absolute neutrophil count (NEUT) ≥1.5 × 10⁹/L (without blood transfusion or use of hematopoietic stimulating factors within 7 days prior to examination); 3. Platelet count (PLT) ≥100 × 10⁹/L (without blood transfusion or use of hematopoietic stimulating factors within 7 days prior to examination); 4. Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN); 5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 × ULN; 6. Serum creatinine (CR) ≤1.5 × ULN or creatinine clearance (CCr) ≥60 mL/min (calculated using the standard Cockcroft-Gault formula); 7. Serum albumin ≥30 g/L; 8. Prothrombin time (PT) ≤1.5 × ULN (not receiving anticoagulant therapy); 9. Activated partial thromboplastin time (APTT) ≤1.5 × ULN (not receiving anticoagulant therapy); 10. International normalized ratio (INR) ≤1.5 × ULN (not receiving anticoagulant therapy); 11. Left ventricular ejection fraction (LVEF) ≥50% assessed by echocardiography; 12. QTc interval ≤480 ms on 12-lead electrocardiogram. 10. Female participants of childbearing potential must agree to use contraceptive measures (e.g., intrauterine device, contraceptive pills, or condoms) during the study and for 6 months after study completion; serum pregnancy test must be negative within 7 days prior to study enrollment, and participants must not be breastfeeding. Male participants must agree to use contraceptive measures during the study and for 6 months after study completion.
Exclusion criteria
Participants meeting any of the following criteria will not be enrolled in this study: 1. Female who has received any form of prior antitumor therapy (chemotherapy, radiotherapy, molecular targeted therapy, or endocrine therapy). 2. Currently receiving other antitumor drug therapy. 3. Has bilateral invasive breast cancer, inflammatory breast cancer, or occult breast cancer. 4. Clinical stage IV breast cancer. 5. Breast cancer not confirmed by histopathology. 6. Has had other malignancies within the past 5 years (excluding cured carcinoma in situ of the cervix). 7. Has severe organ dysfunction involving the heart, liver, kidney, or other major organs. 8. Has conditions that may affect drug administration and absorption, such as dysphagia, chronic diarrhea, intestinal obstruction, etc. 9. Has participated in another clinical drug trial within the past 4 weeks. 10. Has a known history of allergy to any component of the study drugs; has a history of immunodeficiency, including positive test for human immunodeficiency virus (HIV), positive test for hepatitis C virus (HCV), active hepatitis B, or other acquired or congenital immunodeficiency diseases, or has undergone organ transplantation. 11. Has a history of any cardiac disease, including arrhythmia requiring medical treatment or clinically significant, myocardial infarction, heart failure, or any other cardiac condition deemed by the investigator to be inappropriate for participation in this study. 12. Is pregnant or breastfeeding; is a woman of childbearing potential with a positive baseline pregnancy test; or is a woman of childbearing potential who is unwilling to take effective contraceptive measures during the entire study period. 13. Has concomitant diseases (including but not limited to severe hypertension, severe diabetes, active infections, etc., not controlled by medication) that, in the investigator's judgment, may pose potential harm to the participant's health or affect study completion. 14. Has a definite history of neurological or psychiatric disorders, including epilepsy or dementia. 15. Is considered by the investigator to be unsuitable for participation in this study for any other reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed tpCR | At surgery after completion of six treatment cycles, approximately 24 weeks after randomization | Total pathological complete response (tpCR) will be assessed by the investigator after completion of neoadjuvant therapy. tpCR is defined as the percentage of participants with no evidence of invasive cancer in the breast primary tumor and no involvement of regional lymph nodes on microscopic examination after resection of the primary tumor (i.e., ypT0/Tis, ypN0 per AJCC 8th edition). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed bpCR | At surgery after completion of six treatment cycles, approximately 24 weeks after randomization | Breast pathological complete response (bpCR) rate is defined as the percentage of participants with no evidence of invasive cancer in the breast primary tumor on microscopic examination after resection of the primary tumor (i.e., ypT0/Tis per AJCC 8th edition), as assessed by the investigator after completion of neoadjuvant therapy. This outcome is reported as a percentage of participants. |
| Objective Response Rate (ORR) | From randomization through surgery after six treatment cycles, approximately 24 weeks | ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) as determined by the investigator according to RECIST version 1.1 during neoadjuvant therapy. |
| Changes in Ki-67 Expression | From baseline through surgery after completion of six treatment cycles, approximately 24 weeks | Changes in Ki-67 expression are defined as the change from baseline in the percentage of Ki-67-positive tumor cells assessed by immunohistochemistry (IHC) at baseline and after completion of neoadjuvant therapy, and are reported as percentage change (%). |
| Residual Cancer Burden (RCB) Index | From randomization through surgery after six treatment cycles, approximately 24 weeks | Residual Cancer Burden (RCB) index is a continuous composite measure derived by combining the primary tumor residual tumor dimensions (mm × mm), residual tumor cellularity (%), proportion of ductal carcinoma in situ (%), number of positive lymph nodes, and size of the largest lymph node metastasis (mm) using the standard RCB formula, and is reported as a unitless score, assessed pathologically after completion of neoadjuvant therapy and surgery. |
| Patient-Reported Outcomes (PRO) | From baseline through surgery after completion of six treatment cycles, approximately 24 weeks | Patient-Reported Outcomes (PRO) will be assessed using the EORTC QLQ-C30 questionnaire according to the EORTC scoring manual. The questionnaire encompasses multiple dimensions: global health status, functional scales (physical, role, emotional, cognitive, and social functioning), symptom scales (fatigue, nausea/vomiting, and pain), and single-item measures (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). Raw scores for each dimension are calculated as the mean of the item responses contributing to that scale and are linearly transformed to a 0-100 scale. For global health status and functional scales, higher scores indicate better functioning/quality of life; for symptom scales, higher scores indicate greater symptom severity. Changes in scores for each HRQoL dimension from baseline will be analyzed at various time points, and are reported as change in score on a 0-100 scale for each dimension. |
| Incidence of Abnormal Physical Examination Findings | Baseline, Day 1 of each treatment cycle, end of treatment (pre-surgery). | Incidence of abnormal physical examination findings, defined as the percentage of participants with abnormal findings on physical examination, reported as a percentage of participants (%). |
| Oxygen Saturation | Baseline, Day 1 of each treatment cycle, end of treatment (pre-surgery). | Oxygen saturation, measured by pulse oximetry, reported as oxygen saturation percentage (SpO₂, %). |
| Vital Signs | Baseline, Day 1 of each treatment cycle, end of treatment (pre-surgery). | Vital signs, including body temperature (°C), systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), and respiratory rate (breaths/min), measured by standardized vital sign monitoring, with each parameter reported in its respective unit. |
| 12-Lead Electrocardiogram Parameters | Baseline, Day 1 of each treatment cycle, end of treatment (pre-surgery). | 12-lead electrocardiogram parameters, including heart rate (beats/min), PR interval (ms), QRS duration (ms), and QTc interval (ms), measured by 12-lead electrocardiogram, with each parameter reported in its respective unit. |
| Echocardiography Parameters | Baseline, Day 1 of each treatment cycle, end of treatment (pre-surgery). | Echocardiography parameters, including left ventricular ejection fraction (LVEF, %), measured by echocardiography, reported as a percentage (%). |
| Incidence of Abnormal Laboratory Test Findings | Baseline, Day 1 of each treatment cycle, end of treatment (pre-surgery). | Incidence of abnormal laboratory test findings, defined as the percentage of participants with abnormal findings on laboratory tests (including hematology, blood chemistry, coagulation, and urinalysis), reported as a percentage of participants (%). |
| Incidence of Adverse Events | From the first dose of study treatment through 30 days after the last dose, approximately 28 weeks | Incidence of adverse events (AEs), including all AEs and serious adverse events (SAEs), graded according to NCI CTCAE v5.0, reported as the percentage of participants (%) with AEs/SAEs and the number of events. |
Contacts
CONTACTLi Ma
Outcome results
None listed