A Study to Evaluate the Safety and Tolerability of Using the SHR-1210 by Advanced Solid Tumor Subjects

Study Overview
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Brief Summary
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This is an open-label, multiple centers, non-randomized, dose escalation phase I trial to evaluate safety and tolerability of SHR-1210 in patients with advanced solid tumors The primary objective is to assess safety and tolerability of SHR-1210 and identify recommended phase II doses of SHR-1210 in patients with advanced solid tumors

Official Title
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An Open-Label, Multiple Centers, Non-randomized, Dose-Escalation Phase 1 Study to Evaluate Safety and Tolerability of SHR-1210 in Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Biological: SHR-1210


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 18-70 years old. Patients with pathologically confirmed solid tumors (mainly lung, nasopharyngeal, esophageal/gastric and liver cancer). Patients with advanced (unresectable or metastatic) solid tumors who failed standard treatment (progressive disease or intolerance, such as to chemotherapy, targeted therapy, or immunotherapy other than those targeting PD-1/PD-L1) or with no effective treatment available. ECOG PS: 0-1. Life expectancy ≥ 12 weeks. With measurable and evaluable lesions according to the RECIST v1.1. Exclusion Criteria: Patients with any active autoimmune diseases or a history of autoimmune diseases (including but not limited to the following: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; adult patients with vitiligo or completely relieved childhood asthma can be enrolled if they do not require any intervention; patients with asthma requiring medical interventions with bronchodilators cannot be enrolled). Patients who are currently using immunosuppressive agents, or systemic or absorbable local hormonal therapies for immunosuppression purposes (> 10 mg/day prednisone or equivalent) and still use the above drugs within 2 weeks prior to enrollment. Patients who are known to be previously allergic to macromolecular protein preparations, or any component of SHR-1210. Patients with clinically symptomatic metastases to central nervous system (e.g., cerebral edema requiring hormonal intervention, or progression of brain metastasis): 1)Patients who have received treatment for brain or meningeal metastasis can be included if they are clinically stable (MRI) for at least 2 months and have discontinued systemic hormonal therapy (> 10 mg/day prednisone or equivalent) for more than 2 weeks; 2)Non-small cell lung cancer patients with brain metastasis, except those requiring local radiotherapy, can be enrolled into 200 mg fixed dose group (refer to Study Design and Schedule of Activities sections). 5. Patients with previous or concurrent malignancies at other sites (except for cured skin basal cell carcinoma and cervical carcinoma in situ). 6. Patients with clinical symptoms or diseases of the heart that are not well controlled, such as (1) > NYHA Class II cardiac failure, (2) unstable angina, (3) myocardial infarct within the past year, (4) clinically significant supraventricular or ventricular arrhythmia requiring treatment or interventions. 7. Patients who have previously received radiotherapy, chemotherapy, hormone therapy, surgery, or molecular targeted therapy with an interval of less than 4 weeks from the completion of the treatment to this study medication (for subjects who have previously received chemotherapy with nitrosourea or mitomycin, the interval from the end of chemotherapy to the study enrollment is less than 6 weeks); patients whose AEs caused by previous treatment have not recovered to CTCAE Grade ≤ 1; patients who are still receiving anti-tumor treatment with traditional Chinese medicine 2 weeks before the study medication. 8. Patients with active infection or unexplained fever > 38.5 °C during screening or prior to the first dose (patients with tumor-induced fever may be enrolled as per the judgment of the investigator). 9. Patients with congenital or acquired immunodeficiency (such as HIV infection), or active hepatitis (hepatitis B: HBsAg, Anti-HBs, HBeAg, Anti-HBc, Anti-HBe, HBV DNA ≥ 104/mL, hepatocyte transaminases, etc.; hepatitis C: HCV antibodies and HCV RNA).

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

Sexes Eligible for Study
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All

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Injection SHR-1210 1mg/kg Cohort<br> | Biological: SHR-1210<br>* A fully human monoclonal immunoglobulin (IgG4 subtype)<br>|
| Experimental: Injection SHR-1210 3mg/kg Cohort<br> | Biological: SHR-1210<br>* A fully human monoclonal immunoglobulin (IgG4 subtype)<br>|
| Experimental: Injection SHR-1210 200mg Cohort<br> | Biological: SHR-1210<br>* A fully human monoclonal immunoglobulin (IgG4 subtype)<br>|
| Experimental: Injection SHR-1210 10mg/kg Cohort<br> | Biological: SHR-1210<br>* A fully human monoclonal immunoglobulin (IgG4 subtype)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events (AEs) | The safety assessment documented in this clinical study included any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of an investigational product, which were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version [v] 4.03 2010). | From the time the participants signed the informed consent to 90 days after the final dose (Up to 3 years and 7 months) | 
| Number of Participants Experiencing Severe AEs (SAEs) | The safety assessment documented in this clinical study included any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of an investigational product, which were monitored per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version [v] 4.03 2010). | From the time the participants signed the informed consent to 90 days after the final dose (Up to 3 years and 7 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Area Under the Serum Concentration-time Curve to infinite time (AUC 0-inf) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Area Under the Serum Concentration-time Curve from dosing to the time of the last measured concentration (AUC 0-last) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Time to Maximum Concentration (Tmax) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Half-life (T½) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Clearance (Cl) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Volume of distribution (Vd) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Mean Residence Time (MRT) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| C(ss, Max) of SHR-1210 after Multiple Dosing |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| C(ss, Min) of SHR-1210 after Multiple Dosing |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Accumulation ratio based on Cmax (Rac, Cmax) for SHR-1210 |  | PK blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| PD-1 receptor occupancy (RO) for SHR-1210 | Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. | PD blood samples are collected multiple times on Cycle 1 (each cycle is 28 days) Day1, Day 8, Day 15, Day 22, Cycle 2 Day 1, Since Cycle 2, every 3 cycle Day 1, and the day disease progression (Up to 3 years and 7 months). | 
| Number of Participants with Anti-drug Antibodies (ADAs) for SHR-1210 | ADAs: Immunogenicity was summarized by the number and percentage of participants who developed detectable treatment-emergent ADAs. | Blood samples for ADAs analysis are collected on Cycle 1 (each cycle is 28 days) Day1 to the end of treatment (Up to 3 years and 7 months). | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants in the study whose best overall response was either complete response (CR) or partial response (PR) as assessed by investigators based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. | Up to 3 years and 7 months | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants in the study whose best overall response was either CR, PR or stable disease (SD) as assessed by investigators based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. | Up to 3 years and 7 months | 
| Progression-free survival (PFS) | PFS was defined as the time from the date of first study dose to disease progression or death whichever occurs first. Participants without an event (no disease progression or death) were censored at the date of last tumor assessment. Participants with no baseline or post-baseline tumor assessments were censored at Day 1. PFS was based on RECIST v 1.1 and the results of Investigator evaluations. Median PFS was calculated by Kaplan-Meier method. | Up to 3 years and 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-1/PD-L1 Advanced Solid Tumor Immunotherapy