Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series Study- Neoadjuvant Therapy

Study Overview
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Brief Summary
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The purpose of this study is to establish a prospective, single-center platform research based on clinical subtypes to explore precision neoadjuvant therapy in patients with operable breast cancer who met the indications for neoadjuvant chemotherapy and by the update of basic translational research in the center, especially the refinement of typing, the discovery of new targets and the development of novel targeted drugs, verified the effectiveness of new targeted drugs in neoadjuvant therapy.

Detailed Description
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FASCINATE-N is a platform that will compare the efficacy of novel drugs alone or in combination with standard chemotherapy with the efficacy of standard therapy alone. The goal is to identify improved treatment regimens for subsets on the basis of clinical subtyping. In this trial, breast cancer patients eligible for inclusion can be randomly divided into the precision treatment group and conventional neoadjuvant chemotherapy group according to molecular typing and subtyping. The research therapy arm can be updated with the update of basic translational research in our center, especially the refinement of typing, the discovery of new targets and the development of novel targeted drugs. As described for previous adaptive trials, regimens that show to be more effective than standard therapy will graduate from the trial with their corresponding biomarker signature(s). Regimens will be dropped if they show a low probability of improved efficacy with any biomarker signature. New drugs will enter as those that have undergone testing complete their evaluation.

Official Title
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Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series Study- Neoadjuvant Therapy (FASCINATE-N)

Conditions
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Triple-Negative Breast Cancer (TNBC), Breast Neoplasm, Breast Cancer, Breast Tumors, HER2-positive Breast Cancer, HER2-negative Breast Cancer, Hormone Receptor Positive Tumor, Hormone Receptor Negative Tumor, Early-stage Breast Cancer, Locally Advanced Breast Cancer

Intervention / Treatment
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* Drug: Dalpiciclib
* Drug: Pyrotinib
* Drug: SHR-A1811
* Drug: SHR-1316
* Drug: Camrelizumab
* Drug: Trophoblast cell-surface antigen 2 (TROP2) ADC
* Drug: Pertuzumab
* Drug: Trastuzumab
* Drug: Goserelin
* Drug: Letrozole
* Drug: Nab paclitaxel
* Drug: Carboplatin
* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Fluzoparib
* Drug: HER2 ADC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed invasive cancer of the breast and meet the clinical stage T2-4, N1-3, M0 criteria; Age between18-70 years; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; ER, PR and HER2 status were measured by immunohistochemistry (IHC); LVEF≥55%； Definition of SNF subtypes: SNF subtypes confirmed by digital pathology of H&E slices; Triple negative subtyping: On the basis of triple-negative pathological diagnosis, AR, cluster of differentiation 8 (CD8) and Forkhead Box C1 (FOXC1) were combined to define the subtyping; At least one measurable lesion according to RECIST version 1.1 Normal organ and marrow function: Hemoglobin (HB) ≥90 g/L (No blood was transfused within 14 days), Absolute neutrophil count ≥ 1500/μL, Platelets ≥ 75,000/μL, Total bilirubin ≤ 1.5 x ULN), aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 3 x ULN, creatinine < 1 x ULN, endogenous creatinine clearance > 50 ml/min (Cockcroft-Gault formula); Non-pregnant and non-lactating, fertile female subjects were required to use a medically approved contraceptive method for the duration of the study treatment and at least 3 months after the last use of the study drug; Ability to understand and willingness to sign a written informed consent Exclusion Criteria: Previous cytotoxic chemotherapy, endocrine therapy, biological therapy or radiotherapy for any reason; Patients with New York Heart Association (NYHA) grade II or above heart disease (including grade II); Patients with severe systemic infections or other serious diseases; Patients with known allergy or intolerance to the study drug or its excipients; Other malignant tumors in the past 5 years, except cured cervical carcinoma in situ and non-melanoma skin cancer; Pregnant or lactating patients of childbearing age who refused to take appropriate contraceptive measures during the course of the study; Participated in other trial studies within 30 days before the administration of the first dose of the study drug; Patients who were judged by the investigator to be unsuitable for this study.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L1-1<br>If patients were hormone receptor-positive (HR+) and HER2-negative (HER2-) defined as similarity network fusion 1(SNF1) subtype | Drug: Dalpiciclib<br>* an oral cyclin-dependent kinases (CDK) 4/6 inhibitor<br>* Other names: SHR-6390;Drug: Goserelin<br>* goserelin<br>Drug: Letrozole<br>* letrozole<br>|
| Active Comparator: L1-2<br>If patients were HR+HER2- with SNF1 subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>|
| Experimental: L2-1<br>If patients were HR+HER2- with similarity network fusion 2 (SNF2) subtype | Drug: Dalpiciclib<br>* an oral cyclin-dependent kinases (CDK) 4/6 inhibitor<br>* Other names: SHR-6390;Drug: SHR-1316<br>* an anti-programmed death ligand 1 (PD-L1) antibody<br>Drug: Goserelin<br>* goserelin<br>Drug: Letrozole<br>* letrozole<br>|
| Active Comparator: L2-2<br>If patients were HR+HER2- with SNF2 subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>|
| Experimental: L3-1<br>If patients were HR+HER2- with similarity network fusion 3 (SNF3) subtype | Drug: Dalpiciclib<br>* an oral cyclin-dependent kinases (CDK) 4/6 inhibitor<br>* Other names: SHR-6390;Drug: Goserelin<br>* goserelin<br>Drug: Letrozole<br>* letrozole<br>Drug: Fluzoparib<br>* an original poly adenosine diphosphate-ribose polymerase (PARP) inhibitor<br>* Other names: SHR-3162;|
| Active Comparator: L3-2<br>If patients were HR+HER2- with SNF3 subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>|
| Experimental: L4-1<br>If patients were HR+HER2- with similarity network fusion 4 (SNF4) subtype | Drug: Trophoblast cell-surface antigen 2 (TROP2) ADC<br>* anti-TROP2 ADC<br>|
| Active Comparator: L4-2<br>If patients were HR+HER2- with SNF4 subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>|
| Experimental: L4-low-1<br>If patients were HR+HER2-low with SNF4 subtype | Drug: SHR-A1811<br>* an anti-HER2 antibody-drug conjugate (ADC)<br>|
| Active Comparator: L4-low-2<br>If patients were HR+HER2-low with SNF4 subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>|
| Experimental: TN1-1<br>If patients were triple-negative breast cancer with immunomodulatory (IM) subtype | Drug: Camrelizumab<br>* an anti-programmed death-1 (PD1) antibody<br>* Other names: SHR-1210;Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Active Comparator: TN1-2<br>If patients were triple-negative breast cancer with IM subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Experimental: TN2-1<br>If patients were triple-negative breast cancer with basal-like immune suppressed (BLIS) subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>Drug: Fluzoparib<br>* an original poly adenosine diphosphate-ribose polymerase (PARP) inhibitor<br>* Other names: SHR-3162;|
| Active Comparator: TN2-2<br>If patients were triple-negative breast cancer with BLIS subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Experimental: TN3-1<br>If patients were triple-negative breast cancer with androgen receptor positive HER2 activated (AR HER2) subtype | Drug: Pyrotinib<br>* an irreversible dual pan-erbb receptor tyrosine kinase receptor tyrosine kinase (ERBB) inhibitor<br>Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Active Comparator: TN3-2<br>If patients were triple-negative breast cancer with AR HER2 subtype | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Experimental: TN4-1<br>If patients were HR-HER2-low | Drug: SHR-A1811<br>* an anti-HER2 antibody-drug conjugate (ADC)<br>|
| Active Comparator: TN4-2<br>If patients were HR-HER2-low | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Experimental: TN5-1<br>If patients were triple-negative breast cancer with other subtypes | Drug: Trophoblast cell-surface antigen 2 (TROP2) ADC<br>* anti-TROP2 ADC<br>|
| Active Comparator: TN5-2<br>If patients were triple-negative breast cancer with other subtypes | Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>Drug: Epirubicin<br>* Epirubicin<br>Drug: Cyclophosphamide<br>* Cyclophosphamide<br>|
| Experimental: H1-1<br>If patients were HR+HER2+ | Drug: Pyrotinib<br>* an irreversible dual pan-erbb receptor tyrosine kinase receptor tyrosine kinase (ERBB) inhibitor<br>Drug: HER2 ADC<br>* anti-HER2 ADC<br>|
| Active Comparator: H1-2<br>If patients were HR+HER2+ | Drug: Pertuzumab<br>* Pertuzumab<br>Drug: Trastuzumab<br>* Trastuzumab<br>Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<br>|
| Experimental: H2-1<br>If patients were HR-HER2+ | Drug: HER2 ADC<br>* anti-HER2 ADC<br>|
| Active Comparator: H2-2<br>If patients were HR-HER2+ | Drug: Pertuzumab<br>* Pertuzumab<br>Drug: Trastuzumab<br>* Trastuzumab<br>Drug: Nab paclitaxel<br>* Albumin paclitaxel<br>Drug: Carboplatin<br>* Carboplatin<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 rate | through study completion, up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| invasive disease-free survival (iDFS) | To determine three-year invasive disease-free survival (iDFS) among the treatment arms | Three-year Post-surgery Follow-up | 
| Overall response rate (ORR) | Complete response (CR) + partial response (PR) | up to 24 weeks | 
| CTCAE scale (V4.0) | 4) To evaluate the rate of adverse effects of patient by the standard CTCAE scale (V4.0) | through study completion, an average of 1 year | 
| Evaluate gene expression profile during treatment | To measure gene expression profile of baseline and sequential tumor samples during treatment, through RNA-seq platform | through study completion, up to 24 weeks | 
| Number of peripheral blood mononuclear cells (PBMC) count during treatment | To measure number of peripheral blood mononuclear cells (PBMC) count from baseline and sequential blood samples during treatment, through Flow CytoMetry platform | through study completion, up to 24 weeks |