A Phase Ⅰb/Ⅱ Clinical Study of SHR-A1811 Combined With Other Therapies in Patients With HER2 Low Advanced or Metastatic Breast Cancer.

Study Overview
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Brief Summary
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This study aims to evaluate the safety, tolerability, PK and preliminary anti-tumour activity of SHR-A1811 combined with other therapies in patients with HER2 low advanced or metastatic breast cancer.

Official Title
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An Open, Multicenter Phase Ⅰb/Ⅱ Clinical Study of SHR-A1811 Combined With Dalpiciclib, Fulvestrant, Bevacizumab or Letrozole/Anastrozole in Patients With HER2 Low Advanced or Metastatic Breast Cancer.

Conditions
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HER2 Low Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: SHR-A1811 & Dalpiciclib Isethionate Tablets
* Drug: SHR-A1811 & Fulvestrant
* Drug: SHR-A1811 & Bevacizumab injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to give informed consent, signed and dated IRB/EC approved informed consent, willing and able to comply with treatment planning visits, tests and other procedural requirements When signing the informed consent, the age is 18-75 years old (including both ends), female patients who have pathologically documented HER2 low breast cancer ECOG Performance Status of 0 or 1 Patient must have adequate tumor sample for biomarker assessment At least one measurable lesion Adequate organ function Exclusion Criteria: There are untreated or active central nervous system (CNS) tumor metastases There was a third space effusion that could not be controlled by drainage (such as a large number of ascites, pleural effusion and pericardial effusion) Major surgery within 4 weeks prior to enrollment Has multiple primary malignancies within 5 years, excluding cured basal cell carcinoma of skin, cervical carcinoma in situ, papillary thyroid carcinoma, etc Has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out at screening Uncontrolled intercurrent illness Uncontrolled or significant cardiovascular disease Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. According to NCI-CTCAE v5.0 classification, those who have not recovered to grade Ⅰ toxicity caused by previous anti-tumour treatment

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: Parallel Assignment
Interventional Model Description: An open, multicenter, dose-finding and dose expansion investigational Phase IB/II clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR-A1811 combined with Dalpiciclib Isethionate Tablets<br> | Drug: SHR-A1811 & Dalpiciclib Isethionate Tablets<br>* SHR-A1811：Lyophilized powder injection, 100mg / bottle, intravenous drip Dalpiciclib Isethionate Tablets：Tablet, 25mg / tablet, 50mg / tablet, 125mg / tablet, 150mg / tablet, oral<br>|
| Experimental: SHR-A1811 combined with Fulvestrant<br> | Drug: SHR-A1811 & Fulvestrant<br>* SHR-A1811：Lyophilized powder injection, 100mg / bottle, intramuscular Fulvestrant：Injection, 5 ml: 0.25g/bottle, intramuscular<br>|
| Experimental: SHR-A1811 combined with Bevacizumab injection<br> | Drug: SHR-A1811 & Bevacizumab injection<br>* SHR-A1811：Lyophilized powder injection, 100mg / bottle, intravenous drip Bevacizumab injection: injection, 100mg / bottle, intravenous drip<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT(Phase I (dose-finding phase) main study endpoint) |  | At the end of cycle 1(each cycle is 28 days for SHR-A1811+ fulvestrant; each cycle is 21 days for SHR-A1811+other therapies. | 
| AE(Phase I (dose-finding phase) main study endpoint) |  | Up to follow-up period, approximately 24 months | 
| Incidence and severity of serious adverse events (SAE)(Phase I (dose-finding phase) main study endpoint) |  | Up to follow-up period, approximately 24 months | 
| Objective response rate(The main end points of the second stage (efficacy expansion stage)) |  | Until progression, assessed up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SHR-A1811 sparse PK concentrations in serum |  | While on study drug up to study completion, approximately 24 months | 
| Dalpiciclib sparse PK concentrations in plasm |  | While on study drug up to study completion, approximately 24 months | 
| Incidence of anti-drug antibodies (ADA) to SHR-A1811 over time |  | Up to follow-up period, approximately 24 months | 
| Incidence of neutralizing antibody (NAb) to SHR-A1811 over time |  | Up to follow-up period, approximately 24 months | 
| Duration of response (DoR) |  | Until progression or death, assessed up to approximately 24 months | 
| Progression-free survival (PFS) |  | Until progression or death, assessed up to approximately 24 months |