A Phase II Trial of Camrelizumab in Combination With Apatinib and Eribulin in Patients With Advanced TNBC

Study Overview
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Brief Summary
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This is a phase II, open-labeled, multi-centered,single-arm, Investigator-initiated clinical trial of camrelizumab (an anti-PD-1 antibody) in combination with apatinib (a VEGFR2 TKI) and eribulin mesylate in patients with advanced triple-negative breast cancer. We will enroll 46 subjects (Simons two stage design). This study aims to evaluate the efficacy and safety of camrelizumab combined with apatinib and eribulin in the treatment of advanced TNBC.

Detailed Description
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This a phase II, open-labeled, multi-centered, single-arm, investigator-initiated clinical trial to assess the efficacy and safety of camrelizumab combination with apatinib and eribulin in female patients age of 18 to 70 with advanced TNBC, and previously treated with at least one line of systemic therapy in the advanced setting. Prior therapy (adjuvant/neoadjuvant/advanced) must have included an anthracycline and a taxane. The number of patients to be included is 46 patients (Simons two stage design). The primary objective is to assess the overall response rate (ORR). All enrolled patients will be treated with camrelizumab 200mg (iv. 3mg/kg for patient whose weight is below 50kg) on day 1 of each 21-day cycle, and apatinib 250mg daily (po, d1-d21), in combination with eribulin mesylate at 1.4 mg/m2 (iv.) on day 1 and day 8 of every 21-day cycle.

Official Title
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An Open-labeled, Single-arm, Investigator-initiated Phase II Trial of Camrelizumab (Anti-PD-1 Antibody) in Combination With Apatinib and Eribulin in Patients With Advanced Triple-Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Camrelizumab
* Drug: Apatinib
* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patients sign the written informed consent. Women aged 18-70. The pathologic diagnosis of unresectable recurrent or metastatic triple-negative breast cancer ［ER-negative(IHC<1%), PR-negative(IHC<1%), HER2-negative（IHC-/+ or IHC++ and FISH/CISH-）］. Patients with at least one measuring lesion that was conformed to RECIST v1.1 standard. Prior therapy (adjuvant/neoadjuvant/advanced) must have included an anthracycline and a taxane in any combination or order and either in the early or metastatic disease setting unless contraindicated for a given patient. The patient can swallow pills. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. With a life expectancy of at least 12 weeks. The results of patient's blood tests are as follows: • Hb≥90g/L; • Plt≥100^9/L; • Serum albumin ≥3g/dL;• Neutrophils≥1.5^9/L; TSH≤ normal upper limit (ULN);• ALT and AST ≤1.5 ULN (liver metastases ≤3 ULN); • TBIL ≤ULN (total bilirubin ≤1.5 ULN in Gilbert's syndrome or liver metastasis subjects);• ALT and AST ≤1.5 ULN (liver metastases ≤3 ULN);• AKP≤ 2.5 ULN; • Renal function within 7 days before the first administration: serum creatinine ≤1.5 ULN or creatinine clearance ≥60mL/min Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose and must be willing to use very efficient barrier methods of contraception for the course of the study through 6 months after the last dose of study treatment. Exclusion Criteria: The subjects had a central nervous system metastases with clinical symptoms. Other clinical trials of drugs were used in the first four weeks before the first dose. Subjects with severe allergic reactions to other monoclonal antibodies. Received other anti-tumor treatments within 28 days before the first dose. A heart condition or disease that is not well controlled. Subjects with treatment history of anti-angiogenesis drugs, or immunotherapy (previous use of anti-PD-1/PD-L1 antibodies was allowed) or eribulin. The subjects had any history of autoimmune disease or any use of systemic glucocorticoid or immunosuppressive medications. Subjects had history of hypertension and poor control with antihypertensive medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg). Urine routine indicated that urine protein ≥ ++, or the 24-hour urine protein quantity ≥ 1.0g. Hereditary or acquired bleeding and thrombotic tendencies (such as hemophilia, coagulation dysfunction, thrombocytopenia, hypersplenism, etc.). Congenital or acquired immune deficiency (such as HIV infection); Receive live vaccine within 4 weeks before or during the study period; Patients who are allergic to or contraindicated to the experimental drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Camrelizumab +Apatinib+Eribulin<br>Camrelizumab 200mg(3mg/kg for patient whose weight is below 50kg) iv Q3W combination with Apatinib 250mg, po, daily (d1-d21)and Eribulin1.4mg/m2 iv d1, d8 Q3W | Drug: Camrelizumab<br>* Camrelizumab 200mg (3mg/kg for patient whose weight is below 50kg) will be administered as an intravenous infusion over 30 minutes every three weeks until unacceptable toxic effects or disease progression or other termination criteria appeared. Patients received up to two years of treatment.<br>Drug: Apatinib<br>* Apatinib 250mg will be administered daily until unacceptable toxic effects or disease progression or other termination criteria appeared. Patients received up to two years of treatment.<br>Drug: Eribulin<br>* Eribulin Mesylate will be administered as a 1.4 mg/m2 intravenous (IV) injection over 2 to 5 minutes on day 1 and day 8 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared. Patients received up to two years of treatment.<br>* Other names: Eribulin Mesylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The propotion of subjects with CR or PR. | 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 dose | 
| Disease Control Rate (DCR) | The propotion of subjects with CR, PR, or SD. | 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 24 months) | 
| One year-OS rate | One year-Overall survival rate | 12 months after the first drug administration | 
| Clinical benefit rate (CBR) | The propotion of subjects with CR, PR, or SD for >=6 months during the study. | 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 (including tumor/stromal PD-L1, stromal PD-1, tumor-infiltrating lymphocytes and tumor-infiltrating B cells, eg) | pre-treatment, up to 24 months |