A Phase 1 Study of HRS8807 Monotherapy and in Combination With SHR6390 in Subjects With ER-Positive, HER2-Negative Metastatic or Locally Advanced Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The study is to assess safety and tolerability of HRS8807 monotherapy and in combination with SHR6390 in subjects with metastatic or locally advanced breast cancer in order to estimate the Dose-Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).

Official Title
-----------------
A Phase 1, Single Arm, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability and Pharmacokinetic of HRS8807 Monotherapy and in Combination With SHR6390 in Subjects With ER-Positive, HER2-Negative Metastatic or Locally Advanced Breast Cancer

Conditions
-----------------
ER-Positive, HER2-Negative Breast Cancer

Intervention / Treatment
-----------------
* Drug: HRS8807
* Drug: HRS8807
* Device: HRS8807、SHR6390
* Drug: HRS8807、SHR6390


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological diagnosis of metastatic or locally advanced breast cancer; Histologically proven diagnosis of ER-positive, HER2-negative; At least 1 line of endocrine therapy in the metastatic or advanced setting that had progressed or intolerance; ≤ 2 lines of chemotherapy for metastatic or advanced disease; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; Expected survival of more than 3 months. Exclusion Criteria: All patients in monotherapy and or in combination wih phase who are known allergic to HRS8807 or SHR6390 ingredient; Presence of symptomatic metastatic visceral disease ; Patients with known active brain metastases; Clinically serious cardiovascular disease; Abnormal electrocardiographic (ECG) with clinical significancy by investigator judgement; Abnormal thyroid function laboratory results; Active infection or unexplained fever >38.5℃ during screening period or on the day of the first dose.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: HRS8807 monotherapy and in combination with SHR6390
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>HRS8807 monotherapy dose escalation | Drug: HRS8807<br>* HRS8807 monotherapy<br>|
| Experimental: Group B<br>HRS8807 monotherapy dose expansion | Drug: HRS8807<br>* HRS8807 monotherapy<br>|
| Experimental: Group C<br>HRS8807 in combination with SHR6390 dose escalation | Device: HRS8807、SHR6390<br>* HRS8807 in combination with SHR6390<br>|
| Experimental: Group D<br>HRS8807 in combination with SHR6390 dose expansion | Drug: HRS8807、SHR6390<br>* HRS8807 in combination with SHR6390<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | Maximum Tolerated Dose (MTD) of HRS8807 monotherapy and in combination with SHR6390 | Change From Baseline at 28 days | 
| RP2D | select the Recommended Phase 2 Dose (RP2D) of HRS8807 monotherapy and in combination with SHR6390 | Change From Baseline at 28 days | 
| Adverse events (AE) and serious AE (SAE) | AEs and SAEs as characterized by frequency and severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE version 5.0]). | Up to 30 days after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| Cmax of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| AUC0-t of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| AUC0-∞ of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| t1/2 of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| Vz/F of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| CL/F of HRS8807 and the major metabolite after single dose of HRS8807 |  | Day 1, Day 2, Day 3 of single dose (3 days before Cycle1) | 
| Tmax,ss of HRS8807 and the major metabolite after multiple dose administration of HRS8807 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Cmax,ss of HRS8807 and the major metabolite after multiple dose administration of HRS8807 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Cmin,ss of HRS8807 and the major metabolite after multiple dose administration of HRS8807 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Rac of HRS8807 and the major metabolite after multiple dose administration of HRS8807 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| AUCss of HRS8807 and the major metabolite after multiple dose administration of HRS8807 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Tmax of HRS8807, the major metabolite and SHR6390 after single dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 1, Day 2, each cycle is 28 days | 
| Cmax of HRS8807, the major metabolite and SHR6390 after single dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 1, Day 2, each cycle is 28 days | 
| AUC0-t of HRS8807, the major metabolite and SHR6390 after single dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 1, Day 2, each cycle is 28 days | 
| Tmax,ss of HRS8807, the major metabolite and SHR6390 after multiple dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Cmax,ss of HRS8807, the major metabolite and SHR6390 after multiple dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Cmin,ss of HRS8807, the major metabolite and SHR6390 after multiple dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| AUCss of HRS8807, the major metabolite and SHR6390 after multiple dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Rac of HRS8807, the major metabolite and SHR6390 after multiple dose administration of HRS8807 and SHR6390 |  | Cycle 1 Day 14, Day 15, each cycle is 28 days | 
| Objective Response Rate (ORR) |  | baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| Duration of Response (DoR) |  | baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant | 
| Progression Free Survival (PFS) |  | baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant |