Immune Therapy in HR-positive/HER2-negative Metastatic Breast Cancer(ENIGMA)

Study Overview
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Brief Summary
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This study is a prospective, open-label, phase II clinical study for patients with HR+/HER2- advanced breast cancer.

Detailed Description
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Patients with SNF2 subtype of HR+/HER2- advanced breast cancer confirmed by the Department of Pathology and Key Laboratory of Breast Cancer of Fudan University Affiliated Cancer Hospital are planned to be enrolled. Five treatment arms were set up based on the whether they have exposed to CDK4/6 inhibitors before. The main purpose is to evaluate immune therapy in SNF2 subtype of HR+/HER2- advanced breast cancer and prepare for subsequent randomized controlled phase III clinical studies with larger sample size.

Official Title
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Immune Therapy in HR-positive/HER2-negative Metastatic Breast Cancer

Conditions
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Breast Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: SHR-1316
* Drug: SHR6390
* Drug: Nab paclitaxel
* Drug: SERD
* Drug: AI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females ≥18 years and ≤ 75 years old; Histologically confirmed HR + / HER2- invasive breast cancer (specific definition: immunohistochemical detection of ER> 10% tumor cell positive is defined as ER positive, PR> 10% tumor cell positive is defined as PR positive, ER and / or PR Positive is defined as HR positive; HER2 0-1 + or HER2 is ++ but negative followed by FISH detection, no amplification, defined as HER2 negative); Subtype of similarity network fusion-2 (SNF-2) confirmed by the Department of Pathology and Key Laboratory of Breast Cancer of Fudan University Affiliated Cancer Hospital Locally advanced breast cancer (incapable of radical local treatment) or recurrent metastatic breast cancer; Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1); or unmeasurable lytic or mixed (osteolytic + osteoblastic) bone lesions in the absence of measurable lesions; Has adequate bone marrow function: absolute neutrophil count > 1.5x10ˆ9 /L; platelet count > 75x10ˆ9 /L, hemoglobin > 9g/dL; Patients had received no previous chemotherapy or targeted therapy for metastatic disease Has adequate liver function and kidney function: serum creatinine ECOG score ≤ 2 and life expectancy ≥ 3 months; Participants voluntarily joined the study, has signed informed consent before any trial related activities are conducted, has good compliance and has agreed to follow-up. Exclusion Criteria: Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded) for metastatic disease Symptomatic, untreated, or actively progressing CNS metastases(glucocorticoids or mannitol needed to control symptoms); Significant cardiovascular disease(including congestive heart failure, angina pectoris, myocardial infarction or ventricular arrhythmia in the last 6 months); is pregnant or breast feeding; Malignant tumors in the past five years (except cured skin basal cell carcinoma and cervical carcinoma in situ). History of autoimmune disease Positive test for human immunodeficiency virus Active hepatitis B or hepatitis C Uncontrolled pleural effusion and ascites Thyroid dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Cohort 1A<br>In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with SHR1316 (anti-PD-L1) and endocrine therapy. | Drug: SHR-1316<br>* PD-L1 antibody<br>Drug: SHR6390<br>* CDK4/6 inhibitor<br>Drug: SERD<br>* Fulvestrant<br>Drug: AI<br>* aromatase inhibitor<br>|
| Active Comparator: Cohort 1B<br>In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with endocrine therapy. | Drug: SHR6390<br>* CDK4/6 inhibitor<br>Drug: SERD<br>* Fulvestrant<br>Drug: AI<br>* aromatase inhibitor<br>|
| Experimental: Cohort 2A<br>In this cohort, a patient would receive SHR1316 (anti-PD-L1) combined with nab-paclitaxel. | Drug: SHR-1316<br>* PD-L1 antibody<br>Drug: Nab paclitaxel<br>* Albumin bound paclitaxel<br>|
| Active Comparator: Cohort 2B<br>In this cohort, a patient would single nab-paclitaxel. | Drug: Nab paclitaxel<br>* Albumin bound paclitaxel<br>|
| Other: Cohort 2C<br>In this cohort, a patient would receive SHR6390(CDK4/6 inhibitor) combined with fulvestrant. | Drug: SHR-1316<br>* PD-L1 antibody<br>Drug: SERD<br>* Fulvestrant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | time to progressive disease (according to RECIST1.1) | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | The proportion of participants whose best outcome is complete remission or partial remission (according to RECIST1.1) | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years) | 
| CBR | the percentage of subjects with CR+PR+SD and last more than 24 weeks in all of the | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years) | 
| OS | time to death due to any cause | Randomization to death from any cause, through the end of study (approximately 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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first-line therapy