A Trial of HRS-8080 Tablets in Metastatic or Local Advanced Breast Cancer of Adults

Study Overview
=================
Brief Summary
-----------------
The study is being conducted to evaluate the tolerance, and safety of HRS-8080 tablets monotherapy and combined with other anti-cancer therapy for metastatic or local advanced breast cancer in adults. To explore the reasonable dosage of HRS-8080 tablets for metastatic or local advanced breast cancer.

Official Title
-----------------
A Single-arm, Open-label and Multi-center Phase I Study on Safety, Tolerance and Pharmacokinetics of HRS-8080 Tablets Monotherapy and Combined With Other Anti-cancer Therapy in Patients With Metastatic or Local Advanced Breast Cancer

Conditions
-----------------
Metastatic or Local Advanced Breast Cancer of Patients

Intervention / Treatment
-----------------
* Drug: HRS-8080 tablets、SHR 6390 tablets、Abemaciclib、Everolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ECOG performance status score: 0-1; Histopathologically documented local advanced or metastatic breast cancer ; Female of not childbearing potential must the related requirement; During or after the last systematic therapy before enrolment, disease progression occurred with clinical or radiographical documentation; Adequate organ functions as defined; Ability to understand and voluntarily agrees to participate by giving written informed consent for the study. Exclusion Criteria: For the case of symptomatic visceral metastasis, the investigators judged that it was not suitable to use relevant treatment; patients with active brain metastasis (without medical control or with clinical symptoms), cancerous meningitis, spinal cord compression, or patients with a history of primary tumors of the central nervous system ; History of clinically significant cardiovascular or cerebrovascular diseases; The subject has one of many factors affecting oral drugs; Active infection or fever with unknown cause > 38.5 °C; Active autoimmune diseases, History of immunodeficiency, including positive HIV serum test result and other acquired or congenital immunodeficiency diseases, or history of organ transplantation; Known history of allergy to study drug ingredients.

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
Intervention Model: Single Group Assignment
Interventional Model Description: HRS-8080 tablets monotherapy and combined with other anti-cancer therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Group<br>Firstly Dose Escalation and Dose Expansion of HRS-8080 monotherapy should be conducted. After RP2D and MTD of the HRS-8080 monotherapy were confirmed, Dose Escalation and Dose Extension of HRS-8080 in combination with other anti-cancer treatment would be completed, including SHR 6390, or Abemaciclib, or Everolimus. | Drug: HRS-8080 tablets、SHR 6390 tablets、Abemaciclib、Everolimus<br>* During HRS-8080 monotherapy period, the dose of HRS-8080 would be increasing. In the combination therapy period, HRS-8080 will be administered at flat dose of RP2D-1 and RP2D.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | The Maximum tolerated dose of HRS-8080 monotherapy or in combination with SHR-6390 / Abemaciclib / Everolimus | up to 28 days | 
| Recommended phase II dose | The Recommended phase II dose of HRS-8080 monotherapy or in combination with SHR-6390 / Abemaciclib / Everolimus | up to 28 days | 
| Incidence and severity of adverse events (AEs)/serious adverse events (SAEs) | Incidence and severity of adverse events (AEs)/serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | up to 30 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| Tmax | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. etc. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| AUC0-t | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| Cmax,ss | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| Tmax,ss | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| Cmin,ss | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| AUCss | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| Rac | PK parameters of multiple doses of HRS-8080 monotherapy. HRS-8080 in combination therapy, SHR-6390, Abemaciclib and Everolimus. | 0.5 hour before first dose of first treatment period to the 0.5 hour before first dose of fifth treatment period | 
| ORR | Objective Response Rate, Preliminary Efficacy endpoints of HRS-8080 monotherapy or in combination with SHR-6390, Abemaciclib or Everolimus in treatment of patients with metastatic or local advanced breast cancer | from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 8 months | 
| BOR | Best Overall Response, Preliminary Efficacy endpoints of HRS-8080 monotherapy or in combination with SHR-6390, Abemaciclib or Everolimus in treatment of patients with metastatic or local advanced breast cancer | from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 8 months | 
| DoR | Duration of response, Preliminary Efficacy endpoints of HRS-8080 monotherapy or in combination with SHR-6390, Abemaciclib or Everolimus in treatment of patients with metastatic or local advanced breast cancer | from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 8 months | 
| DCR | Disease control rate, Preliminary Efficacy endpoints of HRS-8080 monotherapy or in combination with SHR-6390, Abemaciclib or Everolimus in treatment of patients with metastatic or local advanced breast cancer | from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 8 months | 
| PFS | Progression-free survival, Preliminary Efficacy endpoints of HRS-8080 monotherapy or in combination with SHR-6390, Abemaciclib or Everolimus in treatment of patients with metastatic or local advanced breast cancer | from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 8 months |