Clinical Study of JS007 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is an open label, phase Ia clinical study to evaluate the safety, tolerability, pharmacokinetic (PK) profile, pharmacodynamic (PD) profile, immunogenicity and preliminary efficacy of JS007 in the patients with advanced solid tumors who have progressed after standard of care, or lack of effective standard therapeutic regimen. This study is divided into two periods: dose escalation period, dose expansion period.

Official Title
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A Phase Ia Study to Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Single-dose and Multiple-dose Of JS007 Injection In Patients With Advanced Solid Tumors

Conditions
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Patients With Advanced Solid Tumors

Intervention / Treatment
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* Biological: JS007


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients with age of 18 75 years; Signed informed consent form; Confirmed histological or cytological diagnosis of advanced or recurrent solid tumor with previous standard therapy failure, no available standard therapy or refusal of standard therapy; Consent to provide tumor tissue (FFPE archival sample within 2 years, or newly obtained tissue blocks, or unstained slides from FFPE); Having at least one measurable lesion in accordance with the response evaluation criteria in solid tumors (RECIST V1.1). Life expectancy ≥ 3 months; Eastern Cooperative Oncology Group (ECOG) Performance Status score 0 or 1 (Appendix 1); Functional indicators of organs must fulfill the following criteria: i. White blood cell ≥ 2.5 × 109/L ii. Neutrophils ≥ 1.5 × 109/L iii. Platelets ≥ 85 × 109/L iv. Hemoglobin ≥ 90 g/L v. Blood creatinine ≤ 1.5 × ULN, or creatinine clearance > 40 ml/min (calculated according to Cockcroft-Gault formula, see Appendix) vi. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN (for known liver metastases: AST and ALT ≤ 5×ULN) vii. Total bilirubin ≤ 1.5 × ULN (For subjects with Gilbert's Syndrome or known liver metastases, ≤ 2×ULN is acceptable) Exclusion criteria: The patient with metastasis to the central nervous system (CNS); The patient requires systemic steroids or anti-convulsant drugs, or patients with risk of intracerebral hemorrhage judged by the investigator; Patients with primary CNS tumor or meningeal metastasis; Having used systemic anticancer therapy, including radiotherapy, chemotherapy, hormone therapy, surgery, or molecular targeted therapy, within 4 weeks prior to the first dose, or all adverse events except hair loss have not recovered to CTCAE Grade 1 or below; Having other not curable cancers in the past 5 years, excluding the cured or treatable ones, such as basal skin carcinoma, squamous cell skin carcinoma, superficial bladder carcinoma, prostate carcinoma in situ, cervical carcinoma in situ, breast carcinoma in situ, etc; Active autoimmune diseases required systemic treatment in the past 2 years, excluding vitiligo, type I diabetes, and autoimmune thyroiditis indued hypothyroidism that is curable by thyroid hormone replacement therapy; Active tuberculosis (TB); Confirmed infection of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS); Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV): HBsAg positive and HBV DNA ≥ 1000 IU/mL; Positive test results of HCV RNA. Women who are pregnant or breastfeeding; Patients who are unavailable for venipuncture and/or intolerable for intravenous catheterization; Interstitial lung disease; History or basis of any clinically significant cardiovascular diseases as follows: abnormal electrocardiogram indicating additional risk for patients at the discretion of investigator; history of congestive heart failure (CHF) of grade III or above as documented by New York Heart Association (NYHA) criteria; history of cerebral infarction or myocardial infarction within 3 months prior to first dose; uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg); unstable angina; serious uncontrolled arrhythmia; baseline left ventricular ejection fraction (LVEF) < 50% or cardiac wall motion abnormalities identified by echocardiogram (ECHO). Patients accepting other study drugs or anti-infective vaccine (e.g., influenza vaccine, and varicella vaccine) within 28 days prior to the first dose, and COVID-19 （Corona Virus Disease 2019）vaccine is permitted Patients with anti-tumor vaccine therapy within 3 months prior to the first dose, and prophylactic HPV（human papilloma virus） vaccine is permitted; Previous treatment with anti-CTLA-4 drugs; Patients accepting systemic corticosteroids treatment at the doses of immunosuppressive effects (prednisone > 10 mg/day or equivalent level) within 2 weeks before the first dose; patients accepting immunosuppressive agents or glucocorticoids (at doses equivalent to prednisone > 10 mg/day) within 2 weeks before the first dose. Note: Epinephrine replacement therapy (equivalent to prednisone ≤ 10 mg/day) is allowed for patients without active immune disorder . Topical, intraocular, intra-articular, intranasal, and inhaled corticosteroids, which lead to (low systemic absorption, are allowed; short-term corticosteroids treatment is allowed for prophylactic therapy (e.g., be allergic to contrast media) or non-autoimmune diseases (e.g., delayed hypersensitivity reactions after exposure to allergens). Patient accepting any antitumor traditional Chinese patent medicine within 2 weeks prior to the first dose (any antitumor traditional Chinese patent medicine is prohibited during this study). Active infection requiring systematic treatment/antibiotics. Patient accepting intravenous anti-infective therapy with one week prior to the first dose or undergoing systematic anti-infective agents ≥ 7 days; Received live attenuated vaccines within 4 weeks prior to the first dose, or plan to receive live attenuated vaccines during the study; Allergic to any component of JS007; Patients are not ineligible if meet at least one of the following conditions prior to the first dose : i. Major surgery requiring general anesthesia within 4 weeks prior to the first dose; ii. Surgery requiring local/epidural anesthesia within 72 hours prior to the first dose; iii. Skin biopsy requiring local anesthesia within 1 hour prior to the first dose. Patients who are not appropriate for this trial due to other reasons at the discretion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JS007<br> | Biological: JS007<br>* JS007 only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | The maximum tolerated dose (MTD) is defined as the highest dose at which DLT （Dose-Limiting Toxicity）occurs in <1/3 subjects | Up to 12 approximately months | 
| DLT | DLT is defined as any of the specified toxicities evaluated as at least possibly related with the study drug within 21 days after the first dose (NCI-CTCAE v5.0) | 21 days after first infusion of study drug | 
| Adverse Events | AE is assessed according to NCI-CTCAE 5.0 | Up to 12 approximately months | 
| Serious Adverse Events | SAE（Serious adverse event） is assessed according to NCI-CTCAE 5.0 | Up to 12 approximately months | 
| Incidence of immune-related adverse events (irAE) | IrAE is assessed according to NCI-CTCAE 5.0 | Up to 12 approximately months | 
| severity of immune-related adverse events (irAE) | IrAE is assessed according to NCI-CTCAE 5.0 | Up to 12 approximately months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| peak concentration (Cmax) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters peak concentration (Cmax); | Up to 12 approximately months | 
| trough concentration (Ctrough) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters trough concentration (Ctrough) | Up to 12 approximately months | 
| time to peak (Tmax) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters time to peak (Tmax); | Up to 18 approximately months | 
| area under the plasma drug concentration-time curve (AUC0-t ) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters area under the plasma drug concentration-time curve (AUC0-t ) | Up to 12 approximately months | 
| area under the plasma drug concentration-time curve (AUC0-inf) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters area under the plasma drug concentration-time curve (AUC0-inf); | Up to 12 approximately months | 
| elimination half-life (t1/2) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters elimination half-life (t1/2) | Up to 12 approximately months | 
| clearance rate (CL) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters clearance rate (CL); | Up to 12 approximately months | 
| apparent volume of distribution(Vd) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; apparent volume of distribution(Vd) | Up to 12 approximately months | 
| volume of distribution (Vss) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters volume of distribution (Vss) | Up to 12 approximately months | 
| mean retention time (MRT) | Pharmacokinetic (PK) profile: drug concentration in individual subject at different time points after administration; pharmacokinetic parameters mean retention time (MRT) | Up to 12 approximately months | 
| The number of lymphocyte in peripheral blood before and after administration | The number of lymphocyte in peripheral blood before and after administration | Up to 12 approximately months | 
| The proportion of lymphocyte in peripheral blood before and after administration | The proportion of lymphocyte in peripheral blood before and after administration | Up to 12 approximately months | 
| anti-drug body (ADA) | incidence of anti-drug body (ADA) | Up to 12 approximately months | 
| neutralizing antibody (Nab) | incidence of neutralizing antibody (Nab) | Up to 12 approximately months | 
| neutralizing antibody (Nab) | concentration of neutralizing antibody (Nab) | Up to 12 approximately months |