Study of Utidelone Based Neoadjuvant Treatment on Early High-risk or Locally Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this clinical trial is to evaluate the efficacy and safety of Utidelone based regimen as neoadjuvant treatment With High-risk Early-stage or Locally Advanced Breast Cancer.

Detailed Description
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This is a single arm, multi-center study,three-cohort, prospective phase II study which will enroll 181 high-risk early-stage or locally advanced breast cancer patients.

Official Title
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Study of Utidelone Based Neoadjuvant Treatment on Early High-risk or Locally Advanced Breast Cancer

Conditions
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Breast Cancer, Neoadjuvant Therapy

Intervention / Treatment
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* Drug: Utidelone
* Drug: Carboplatin
* Drug: Epirubicin
* Drug: Trastuzumab
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients who will receive initial treatment, 18-70 years of age； Newly diagnosed high-risk early stage (T1c-2, N1; T2, N0) and locally advanced (T1c-2, N2-3; T3-4, N0-3) breast cancer (tumor stage II, III), in which HR+/HER2- T2, N0 patients need to be accompanied by high-risk factors (histological grade 3 or Ki67 ≥ 20%). Triple negative breast cancer(TNBC), HER2 positive (Immunohistochemical(IHC)3+; IHC 2+, FISH amplification) breast cancer, HR negative HER2 IHC 2+ and undetermined result of FISH, HR positive HER2 negative (IHC 0,1+; 2+, FISH amplification) breast cancer confirmed by pathological test. Eastern Cooperative Oncology Group(ECOG) performance status 0 or 1 The blood routine examination was basically normal (CTCAE ≤ 1) within one week before enrollment (based on the normal values of each research center laboratory). No Human Granulocyte Colony Stimulating Factor(rhGCSF) or blood transfusion/erythropoietin(EPO) or other drugs were used within 14 days prior to enrollment. White blood cell count (WBC) ≥ 4 x109 / L; Neutrophil count (ANC) > 1.5x109 / L; Platelet count (PLT) ≥ 100×109/L Hemoglobin(Hb) ≥ 100g/L. The blood biochemistry examination was basically normal (CTCAE ≤ 1) within one week before enrollment (based on the normal values of each research center laboratory) Serum total bilirubin ≤ Upper limit of normal value(ULN)； Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 1.5×ULN； Alkaline phosphatase ≤ 2.5×ULN； Serum creatinine ≤ 1.5×ULN. Color Doppler echocardiography left ventricular Ejection fraction (LVEF) ≥ 55% Female patients with fertility must agree to use effective contraceptive methods during the study period and within 6 months of the last study medication. The Pregnancy test (urine or serum) must be negative Be willing and able to provide written informed consent/assent for the trial. Exclusion Criteria: Primary stage IV breast cancer； Inflammatory breast cancer; Bilateral primary breast cancer (including invasive cancer and carcinoma in situ)； Previous anti-cancer treatment or radiotherapy for any malignant tumor, excluding cured cervical Carcinoma in situ, skin Basal-cell carcinoma and squamous cell carcinoma. Receive any sex hormone treatment (such as contraceptives, ovarian hormone replacement therapy, etc.), except for Ovarian function suppression（OFS）fertility protection, or any hormone drugs (such as Raloxifene, tamoxifen, or other selective estrogen receptor modulators) to treat osteoporosis or prevent breast cancer； The patient has undergone major surgery unrelated to breast cancer within 4 weeks before treatment or has not yet fully recovered; Symptomatic peripheral neuropathy CTCAE 5.0 grade ≥ 2 Serious cardio cerebral Vascular disease, including but not limited to the followings: History of congestive heart failure or systolic dysfunction (LVEF<50%); Angina pectoris requiring anti angina drugs; High risk uncontrolled arrhythmias or severe conduction abnormalities, such as ventricular arrhythmias that require clinical intervention, II-III degree atrioventricular block, etc; Under resting state, the average corrected Q-T interval(QTcF) of three 12 lead electrocardiogram examinations is>470ms; Clinically significant heart valve disease with cardiac dysfunction; Hypertension that cannot be controlled; History of myocardial infarction Allergic to any component of any drug in this protocol. Those who are not suitable for using Corticosteroid. Individuals with active infections who currently require systematic anti infection treatment. History of immune deficiency disease, including positive of HIV/AIDS, or other acquired or congenital immune deficiency diseases, or having a history of organ transplantation. Who had participated in other drug intervention clinical trials within the 28 days of randomization, or who is participating in another clinical trial or is using other investigational treatments. Individuals in pregnancy (positive Pregnancy test) and lactation. Any other comorbidities that interfere with the implementation of the treatment plan, or the researcher evaluate that the subject has a history of other serious systemic diseases, or other reasons lead to the patients is unsuitable to participate in this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study of Utidelone based neoadjuvant treatment on early high-risk or locally advanced breast cancer
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cohort 1 Triple-negative breast cancer<br>Hormone Receptor(HR) negative, Human Epidermal Growth Factor Receptor 2(HER2 )negative breast cancer Drug: Utidelone in combination with carboplatin Utidelone injection 30mg/m2, on days 1-5 of each cycle; Carboplatin ,Area Under Curve(AUC)6, iv, was administered on day 1; One treatment cycle is 21 days, and there are 6 cycles in total. | Drug: Utidelone<br>* Utidelone injection 30mg/m2, on days 1-5 of each cycle<br>Drug: Carboplatin<br>* Carboplatin Area under curve(AUC)6, iv, was administered on day 1<br>|
| Experimental: cohort 2 HR positive, HER2 negative breast cancer<br>HR positive, HER2 negative, Immunohistochemical(IHC)0,1+; 2+, Fluorescence in situ hybridization(FISH)non-amplification breast cancer Drug: Utidelone in combination with Epirubicin Utidelone injection 30mg/m2, on days 1-5 of each cycle; Epirubicin 75mg/m2 was administered on day 1; One treatment cycle is 21 days, and there are 6 cycles in total. | Drug: Utidelone<br>* Utidelone injection 30mg/m2, on days 1-5 of each cycle<br>Drug: Epirubicin<br>* Epirubicin 75mg/m2 was administered on day 1<br>|
| Experimental: cohort 3 HER2 positive (IHC 3+; IHC 2+,FISH amplification) breast cancer<br>Drug: Utidelone in combination with carboplatin, trastuzumab and pertuzumab Utidelone injection 30mg/m2, on days 1-5 of each cycle; Carboplatin Area Under Curve(AUC)6, iv, was administered on day 1; One treatment cycle is 21 days, and there are 6 cycles in total. Trastuzumab 8mg/kg iv in first cycle on day 1, then 8mg/kg in the rest cycles; pertuzumab 840mg/kg iv in first cycle on day 1, then 420mg/kg in the rest cycles. One treatment cycle is 21 days, and there are 6 cycles in total. | Drug: Utidelone<br>* Utidelone injection 30mg/m2, on days 1-5 of each cycle<br>Drug: Carboplatin<br>* Carboplatin Area under curve(AUC)6, iv, was administered on day 1<br>Drug: Trastuzumab<br>* Trastuzumab 8mg/kg iv in first cycle on day 1, then 6mg/kg in the rest cycles<br>Drug: Pertuzumab<br>* Pertuzumab 840mg/kg iv in first cycle on day 1, then 420mg/kg in the rest cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total pathological complete response (etpCR, Pathologic staging after neoadjuvant therapy(yp)T0/is, (yp)N0) | Percentage of patients with absence of invasive neoplastic cells in ipsilateral lymph nodes and breast | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast Pathologic Complete Response ((bpCR, Pathologic staging after neoadjuvant therapy(yp)T0/is) | Percentage of patients whose pathological evaluation of hematoxylin and eosin-stained breast samples do not show any residual invasive carcinoma | 24 months | 
| Event Free Survival(EFS) of 2 years | Time from the first dose of study intervention administration to any of the following events: progression of disease that precludes surgery, local or distant recurrence after surgery, second primary malignancy (breast or other invasive cancers), or death due to any cause. | 24 months | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Graded according to the Common Terminology Criteria for Adverse Event (CTCAE) grade and changes in CTCAE grade | Through study completion，an average of 1 year | 
| Patient reported outcome (PRO) | National Cancer Center of China-Breast Cancer-A 1.0 (NCC-BC-A 1.0) during the study was used to assess the quality of life；The minimum to maximum values: 0 , 100 Meaning: the higher scores mean a better outcome. | Through study completion，an average of 1 year | 
| Patient reported outcome (PRO) | The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-chemotherapy-induced peripheral neuropathy(CIPN) twenty-item scale (QLQ-CIPN20) was used to assess the quality of life. | Through study completion，an average of 1 year |