A Trial of SHR-1210 (an Anti-PD-1 Antibody) in Combination With Apatinib in Patients With Advanced TNBC

Study Overview
=================
Brief Summary
-----------------
This is a Phase II, Open-labeled, Randomised, Parallel, Non-comparative, Two-arms, Investigator-initiated Clinical Trial of SHR-1210 (Anti-PD-1 Antibody) in Combination With Apatinib (VEGFR2 inhibitor) in Subjects with Advanced Triple Negative Breast Cancer. Subjects with advanced Triple Negative Breast Cancer will be recruited. Patients will be randomised to two treatment arms of this study. One arm is SHR-1210 combination with apatinib daily dosing, and the other arm is SHR-1210 combination with apatinib intermittent dosing; each arm will enrolle10-29 subjects (Simons two stage design). This study aims to evaluate the efficacy and safety of SHR-1210 combination with apatinib in the treatment of advanced TNBC.

Official Title
-----------------
A Phase II, Open-labeled, Randomised, Non-comparative, Two-arms Investigator-initiated Clinical Trial of SHR-1210 (Anti-PD-1 Antibody) in Combination With Apatinib in Subjects With Advanced Triple Negative Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: SHR-1210
* Drug: Apatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patients signed the written informed consent Women aged 18-70. The pathologic diagnosis of recurrent metastatic triple negative breast cancer ［ER-negative(IHC<1%), PR-negative(IHC<1%), HER2-negative（IHC-/+ or IHC++ and FISH/CISH-）］. At least one measuring lesion that conforms to RECIST v1.1 standard. The number of chemotherapy lines in the metastatic phase was <3 line. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. Have a life expectancy of at least 12 weeks. Female Subjects of childbearing potential must have a negative serum pregnancy test within 72 hours before the first dose and must be willing to use very efficient barrier methods of contraception for the course of the study through 3 months after the last dose of study treatment. The patients can swallow pills. The results of patients' blood tests are as follows: • Hb≥90g/L; • Plt≥90E+9/L; • Neutrophils≥1.5E+9/L; • ALT and AST ≤ triple of normal upper limit; • TBIL ≤ 1.5 times of normal upper limit; • Creatinine ≤ 1.5 times of normal upper limit. Exclusion Criteria: The subjects had any history of autoimmune disease or any use of systemic glucocorticoid or immunosuppressive medications. Subjects with severe allergic reactions to other monoclonal antibodies. The subjects had a central nervous system metastases with clinical symptoms. History of hypertension and antihypertensive medications are not well controlled. A heart condition or disease that is not well controlled. Subjects had active infections or recent treatment with a systemic immunostimulatory agent (received within the previous 4 weeks). Other clinical trials of drugs were used in the first four weeks of the first medication. Subjects with treatment history of anti-angiogenesis drugs or check-point inhibitors.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR-1210 +Apatinib daily dosing<br>SHR-1210 200mg(3mg/kg for patient whose weight is below 50kg) iv Q2W combination With Apatinib 250mg, po, daily dosing (d1-d14) | Drug: SHR-1210<br>* SHR-1210 200mg (3mg/kg for patient whose weight is below 50kg) will be administered as an intravenous infusion over 30 minutes every two weeks until unacceptable toxic effects or disease progression or other termination criteria appeared.<br>Drug: Apatinib<br>* Apatinib 250mg will be taked daily/intermittent dosing until unacceptable toxic effects or disease progression or other termination criteria appeared.<br>|
| Experimental: SHR-1210+Apatinib intermittent dosing<br>SHR-1210 200mg (3mg/kg for patient whose weight is below 50kg) iv Q2W combination With Apatinib 250mg, po, intermittent dosing(Continuous administration for 7 days every 14 days, d1-d7) | Drug: SHR-1210<br>* SHR-1210 200mg (3mg/kg for patient whose weight is below 50kg) will be administered as an intravenous infusion over 30 minutes every two weeks until unacceptable toxic effects or disease progression or other termination criteria appeared.<br>Drug: Apatinib<br>* Apatinib 250mg will be taked daily/intermittent dosing until unacceptable toxic effects or disease progression or other termination criteria appeared.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Overall Response Rate | from the first drug administration up to the first occurrence of progression or death(up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | adverse events/serious adverse events | from the first drug administration to within 90 days for the last SHR-1210 dose | 
| DCR | Disease Control Rate | from the first drug administration up to the first occurrence of progression or death(up to 24 months) | 
| DoR | Duration of response | from the first drug administration up to the first occurrence of progression or death(up to 24 months) | 
| PFS | Progression-Free-Survival | from the first drug administration up to the first occurrence of progression or death (up to about 5 years) | 
| One year-OS | One year-Overall survival | 12 months after the first drug administration | 
| CBR | Clinical benefit rate | from the first drug administration up to the first occurrence of progression or death(up to 24 months) | 
| TTR | Time to response | from the first drug administration up to one year | 
| Frequencies Of Biomarkers | Biomarkers (PD-L1, PD-1, VEGF-A, eg) in tumor tissue and peripheral blood | pre-dose, and up to two years |