ACHP-THP vs EC-THP as Neoadjuvant Therapy for HER2-positive EBC

Study Overview
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Brief Summary
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Breast cancer is the most common malignant tumor in women. EC-TH is one of the standard chemotherapy regimens for HER-2 positive early breast cancer(EBC). Earlier use of trastuzumab may improve DFS rate. In this study, the investigators want to find out whether ACH-TH regimen compared with the EC-TH regimen in HER2+ EBC could improve the pCR rate in neoadjuvant chemotherapy. We update protocol in Sep 2020, because Pertuzumab is approveled by Chinese goverment and coverd by national insurance, dual target therapy with Trastuzumab and Pertuzumab is the standard therapy for neoadjuvant therapy of HER2-positive EBC patients.

Detailed Description
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Breast cancer is the most common malignant tumor in women. EC-TH is one of the standard chemotherapy regimens for HER-2 positive early breast cancer(EBC). Earlier use of trastuzumab could improve the DFS rate in HER2+ EBC. But due to the cardio-toxicity of both anthracycline and trastuzumab, the investigators usually avoid using these two drugs synchronously. The guidelines do not recommend ECH-TH regemin because of cardiac adverse effect. Doxorubicin liposome(A) has equivalent effect as anthracycline in advaced breast cancer(ABC), lower cardiac toxicity and could be combined use with trastuzumab. In this study, the investigators want to find out whether ACH-TH regimen compared with the EC-TH regimen in HER2+ EBC could improve the pCR rate in neoadjuvant chemotherapy. We update protocol in Sep 2020, because Pertuzumab is approveled by Chinese goverment and coverd by national insurance, dual target therapy with Trastuzumab and Pertuzumab is the standard therapy for neoadjuvant therapy of HER2-positive EBC patients. So now we want to compare ACHP-THP regimen compared with the EC-THP regimen in HER2+ EBC could improve the pCR rate in neoadjuvant chemotherapy.

Official Title
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A Multi-center Randomized Phase II Study of Doxorubicin Liposome Versus Epirubicin Plus Cyclophosphamide Combined With Trastuzumab and Pertuzumab(HP), Followed by Taxon Plus HP as Neoadjuvant Therapy for HER2-positive Early Breast Cancer

Conditions
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Breast Cancer, Neoadjuvant Chemotherapy

Intervention / Treatment
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* Drug: Doxorubicin liposome
* Drug: Cyclophosphamide
* Drug: Trastuzumab
* Drug: Docetaxel
* Drug: Epirubicin
* Drug: Pertuzumab
* Drug: Paclitaxel
* Drug: Paclitaxel-albumin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient, >/= 18 years of age, </= 70 years of age. HER2-positive breast cancer Histologically confirmed invasive breast carcinoma Clinical stage T2-4/N0-3/M0 or node positive at presentation (patients with T1 tumors will not be eligible) Known hormone-receptor status Non previous anti-breast cancer neoadjuvant chemotherapy Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate hematologic, renal and liver function Screening Left ventricular ejection fraction (LVEF) >/= 50% on echocardiogram (ECHO) Adequate organ function Exclusion Criteria: Stage IV (metastatic) breast cancer or bilateral breast cancer History of any prior (ipsi- or contralateral breast cancer except lobular carcinoma in situ) History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other non-breast malignancies with a similar outcome to those mentioned above Cardiopulmonary dysfunction as defined by protocol Current severe, uncontrolled systemic disease Pregnant or lactating women Any known active liver disease, e.g. due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis Concurrent serious uncontrolled infections requiring treatment or known infection with HIV History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or chemotherapy drugs

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

Sexes Eligible for Study
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All

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACHP-THP<br>Doxorubicin liposome（PLD）35 mg/m2 Cyclophosphamide（CTX）600 mg/m2 Trastuzumab：first cycle 8mg/kg，then 6mg/kg Pertuzumab：first cycle 840mg，then 420mg Docetaxel（DOC）75 mg/m2 every 3 weeks paclitaxel (PTX) 175 mg/m2 every 3 weeks or paclitaxel (PTX) 80 mg/m2 every week albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week | Drug: Doxorubicin liposome<br>* PLD<br>* Other names: PLD;Drug: Cyclophosphamide<br>* CTX<br>* Other names: CTX;Drug: Trastuzumab<br>* H<br>* Other names: Herceptin;Drug: Docetaxel<br>* DOC<br>* Other names: Taxotere;Drug: Pertuzumab<br>* P<br>Drug: Paclitaxel-albumin<br>* albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week<br>|
| Active Comparator: EC-THP<br>Epirubicin（EPI）90 mg/m2 Cyclophosphamide（CTX）600 mg/m2 Trastuzumab：first cycle 8mg/kg，then 6mg/kg Pertuzumab：first cycle 840mg，then 420mg Docetaxel（DOC）75 mg/m2 every 3 weeks paclitaxel (PTX) 175 mg/m2 every 3 weeks or paclitaxel (PTX) 80 mg/m2 every week albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week | Drug: Cyclophosphamide<br>* CTX<br>* Other names: CTX;Drug: Trastuzumab<br>* H<br>* Other names: Herceptin;Drug: Docetaxel<br>* DOC<br>* Other names: Taxotere;Drug: Epirubicin<br>* EPI<br>* Other names: EPI;Drug: Pertuzumab<br>* P<br>Drug: Paclitaxel<br>* paclitaxel (PTX) 175 mg/m2 every 3 weeks or paclitaxel (PTX) 80 mg/m2 every week<br>Drug: Paclitaxel-albumin<br>* albumin-bound paclitaxel 260 mg/m2 or albumin-bound paclitaxel 100 mg/m2 every week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response rate (pCR) | Pathological complete response (pCR) in the breast tissue and the lymph node tissue will be assessed upon completion of pre-operative systemic therapy and definitive surgery. | At the time of definitive surgery (approximately 24-36 weeks from first dose of study drug). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | CRR is defined as the proportion of subjects with complete or partial radiographic response of the primary tumor as determined by the central imaging vendor. | Approximately 20-24 weeks from first dose of study drug | 
| Event Free Survival (EFS) | EFS will be defined as the time from random assignment to documentation of the first of the following events: discontinuation of study therapy due to protocol-defined progression prior to surgery; local, regional, or distant recurrence of breast cancer following curative surgery; a new breast cancer; another new onset malignancy; or death as a result of any cause. | Up to 5 years from the date of definitive surgery | 
| Overall Survival (OS) | OS will be defined as the number of days from the day the subject is randomized to the date of the subject's death. | Up to 5 years from the date of definitive surgery. | 
| Incidence of chemotherapy-induced cardiotoxicity | Incidence of chemotherapy-induced cardiotoxicity, according to NCI-CTCAE 4.03 version. | Approximately 20-24 weeks from first dose of study drug | 
| Change From Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index | The EuroQol EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 descriptors are summarized to create a single summary score. An overall utility score is calculated based on these domains, with a range score from 0 (worse health scenario) to a maximum of 1.0 (best health scenario). | First day of treatment (Day 1) up to 6 months during the post-surgery follow-up period (approximately 15 months from first dose of study drug) | 
| Change From Baseline Between Treatment Comparison in Functional Assessment of Cancer Therapy -Breast (FACT-B) | FACT is a modular approach to assess participant health-related quality of life using a 'core' set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FACT-B consisted of the FACT-G (27-item) and a breast-specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much. FACT-B total score = Physical Well-Being + Social/Family Well-Being + Emotional Well-Being + Functional Well-Being + Breast Cancer Subscale. As each of the items ranges from 0-4, the range of possible scores is 0-144, with 0 being the worst possible score and 144 the best. | First day of treatment (Day 1) up to 6 months during the post-surgery follow-up period (approximately 15 months from first dose of study drug) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human epidermal growth factor receptor 2, Pathology complete response