A Study of SHR6390 in Combination With Letrozole or Anastrozole or Fulvestrant in Patients With HR Positive and HER2 Negative Advanced Breast Cancer

Study Overview
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Brief Summary
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This is a phase IB/II clinical trial to evaluate the efficacy and safety of SHR6390 in combination with Letrozole or Anastrozole or Fulvestrant. Patients who have HR positive and HER2 negative recurrent/metastatic breast cancer and have not received systemic anticancer therapy are eligible for study.

Official Title
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A Phase IB/II to Evaluate Efficacy and Safety of SHR6390 in Combination With Letrozole or Anastrozole or Fulvestrant in Patients With HR Positive and HER2 Negative Recurrent/Metastatic Breast Cancer

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: SHR6390
* Drug: Letrozole or anastrozole or Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has the pathologically-confirmed diagnosis of locally recurrent or metastatic, hormone-receptor positive, HER2 negative Breast Cancer. Age: 18 - 75 years old, postmenopausal women.prepostmenopausal women, but should receive Ovary castration. Inclusion Criteria Cohort 1 and Cohort 2 :No prior systemic anti-cancer therapy for advanced HR+ disease. Cohort 3 and Cohort 4 : Patients must satisfy the following criteria for prior therapy: a) Progressed after 2 years during treatment of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre- or perimenopausal. b)Progressed within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre- or perimenopausal. c) Progressed while 6 month after the end of prior aromatase inhibitor therapy for advanced/metastatic breast cancer if postmenopausal, or prior endocrine treatment for advanced/metastatic breast cancer if pre- or perimenopausal. One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy. 4. Eastern Cooperative Oncology Group [ECOG] 0-1 Measurable disease as per Response Evaluation Criterion in Solid Tumors[RECIST] 1.1 5. Adequate organ and marrow function Exclusion Criteria Confirmed diagnosis of HER2 positive disease Patients who received any endocrine therapy as neo/adjuvant therapy for breast cancer are eligible. If the neo/adjuvant therapy of any endocrine therapy , the disease-free interval must be greater than 12 months from the completion of treatment until study entry. Patients who received prior treatment with any CDK4/6 inhibitor, everolimus,fulvestant. Clinically significant cardiovascular and cerebrovascular diseases,including but not limited to severe acute myocardial infarction within 6 months before enrollment, unstable or severe angina, Congestive heart failure (New York heart association (NYHA) class > 2), or ventricular arrhythmia which need medical intervention. Has known active central nervous system metastases.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Part 1)<br>Participants receive SHR6390 (at protocol defined dose levels) in combination with letrozole 2.5 mg or anastrozole 1mg, orally once daily (continuously). | Drug: SHR6390<br>* SHR6390 150 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole or anastrozole or Fulvestrant<br>* Letrozole 2.5mg or anastrozole 1mg, orally once daily (continuously)， or Fulvestrant 500mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle until progressive disease<br>|
| Experimental: Cohort 2 (Part 1)<br>SHR6390 (TBD), in combination with letrozole 2.5 mg or anastrozole 1mg, orally once daily (continuously). | Drug: SHR6390<br>* SHR6390 150 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole or anastrozole or Fulvestrant<br>* Letrozole 2.5mg or anastrozole 1mg, orally once daily (continuously)， or Fulvestrant 500mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle until progressive disease<br>|
| Experimental: SHR6390 + Letrozole or anastrozole (Part 2)<br>SHR6390 (RP2D, recommended Phase 2 dose), in combination with letrozole 2.5 mg or anastrozole 1mg, orally once daily (continuously). | Drug: SHR6390<br>* SHR6390 150 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole or anastrozole or Fulvestrant<br>* Letrozole 2.5mg or anastrozole 1mg, orally once daily (continuously)， or Fulvestrant 500mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle until progressive disease<br>|
| Experimental: SHR6390 + Fulvestrant Cohort 3 (Part 1)<br>SHR6390 (at protocol defined dose levels), in combination with Fulvestrant 500 mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle once daily | Drug: SHR6390<br>* SHR6390 150 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole or anastrozole or Fulvestrant<br>* Letrozole 2.5mg or anastrozole 1mg, orally once daily (continuously)， or Fulvestrant 500mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle until progressive disease<br>|
| Experimental: SHR6390 + Fulvestrant Cohort 4 (Part 1)<br>SHR6390 (TBD), in combination with Fulvestrant 500 mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle once daily | Drug: SHR6390<br>* SHR6390 150 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole or anastrozole or Fulvestrant<br>* Letrozole 2.5mg or anastrozole 1mg, orally once daily (continuously)， or Fulvestrant 500mg intramuscular injection on day 1 and day 15 for the first cycle and then on day 1 for every cycle until progressive disease<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With adverse events (AEs) and serious adverse events (SAEs) at Phase 1 | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v4.03. Up to 24 months. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of SHR6390 |  | Up to 4 weeks | 
| Peak Plasma Concentration (Cmax) of SHR6390 |  | Up to 4 weeks | 
| The time of SHR6390 to reach the maximum concentration (Tmax) |  | Up to 4 weeks | 
| Half-time (t1/2) of SHR6390 |  | Up to 4 weeks | 
| Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ¡Ý30% decrease in the sum of diameters of target lesions) per RECIST 1.1. | Up to approximately 24 months. | 
| Progression-free Survival (PFS) per RECIST 1.1 | PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review or death due to any cause, whichever occurs first. | Up to approximately 24 months. | 
| Disease Control Rate (DCR) per RECIST 1.1 | DCR is defined as the percentage of participants in the analysis population who have a CR, PR or SD per RECIST 1.1. | Up to approximately 24 months. | 
| Number of Participants With adverse events (AEs) and serious adverse events (SAEs) | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v4.03. | Up to approximately 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDK4/6 inhibitor, Breast cancer, Postmenopausal women, Hormone-receptor positive, HER2 negative, Premenopausal women