A Clinical Study on Oncolytic Virus Injection (R130) for the Treatment of Relapsed/Refractory Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
24 participants are expected to be enrolled for this open，Single-armed clinical trial to evaluate the safety and efficacy of the recombinant herpes simplex virus Ⅰ, R130 in patients with relapsed/refractory advanced solid tumors.

Official Title
-----------------
A Clinical Safety and Efficacy Study on Oncolytic Virus Injection (R130) for the Treatment of Relapsed/Refractory Advanced Solid Tumors

Conditions
-----------------
Gastric Cancer, Lung Cancer, Bronchial Cancer, Non Small Cell Lung Cancer, Small Cell Lung Cancer, Sarcoma, Colorectal Cancer, Liver Cancer, Breast Cancer, Pancreatic Cancer, Head and Neck Cancer, Ovarian Cancer

Intervention / Treatment
-----------------
* Drug: Recombinant oncolytic herpes simplex virus type 1 (R130)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with advanced solid tumors clearly diagnosed by histology and/or cytology. Failure of standard treatment or patient unwillingness to receive other antitumor therapy. Age 18 to 75 years. Subjects with ECOG score of 0-2. Expected survival of 3 months or more. Have at least one measurable lesion (according to RECIST 1.1 criteria) that is amenable to intratumoral or intraperitoneal drug delivery. Subjects must have appropriate organ function, and laboratory tests during the screening period must meet the following requirements: a) absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets (PLT) ≥ 80 × 109/L, and hemoglobin (Hb) ≥ 85 g/L; b) serum creatinine (Cr) and blood urea nitrogen (BUN) within 1.5 times the upper limit of normal values; c) serum c) serum total bilirubin (TBIL) ≤ 2 times the upper limit of normal values; d) glutamic aminotransferase (ALT) and glutamic oxalacetic aminotransferase (AST) ≤ 2.5 times the upper limit of normal values; subjects with liver metastases do not exceed 5 times the upper limit of normal values; e) activated partial thromboplastin time (APTT), prothrombin time (PT) within 1.5 times the upper limit of normal values. Any treatment for malignancy, including radiotherapy, chemotherapy and biological agents, must be discontinued 28 days prior to R130 treatment. Eligible patients of childbearing potential must agree to use a reliable method of contraception (hormonal or barrier method or abstinence) with their partner for the duration of the trial and for at least 180 days after the last dose; female patients of childbearing potential must have a negative urine pregnancy test within 7 days prior to enrollment. Subjects voluntarily sign an informed consent form and are in good compliance. Exclusion Criteria: Have had any serious adverse reactions associated with immunotherapy. Subjects with any severe and/or uncontrolled disease, including: a) poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg); b) suffering from class I or higher myocardial ischemia or myocardial infarction, arrhythmia (QTc ≥ 470 ms and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification); c) active or uncontrolled severe infection (≥ CTCAE grade 2 infection); d) Patients with previous organ transplantation, bone marrow transplantation (hematopoietic stem cell transplantation) and severe immune deficiency; e) Urine routine suggesting urine protein ≥++ and confirmed 24-hour urine protein quantification > 1.0 g. Patients with past history of type I diabetes mellitus or HIV. Severe abnormalities in thyroid and cortisol testing; active, known or suspected autoimmune disease requiring systemic therapy. Patients with severe prior interstitial lung changes (as determined by the investigator). Patients with active tuberculosis and a strong positive OT test. Patients with active bleeding or severe coagulation dysfunction. Have had antitumor therapy, including endocrine, chemotherapy, radiotherapy, targeted therapy, immunotherapy and antitumor herbal therapy, 4 weeks prior to the first dose. Have not recovered to CTCAE 4.0 grade rating 0 or 1 level of toxicity after previous antineoplastic therapy. Current active hepatitis B, active hepatitis C, immunodeficiency virus or other active infection of clinical significance. Patients who have undergone surgery of grade 3 or higher or whose surgical wounds have not healed within 4 weeks prior to enrollment. Pregnant, lactating and planning to have children within six months. Subjects who, in the judgment of the investigator, are unsuitable for participation in this trial for any reason.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R130 Treatment Group<br>Every 7-14 days,1-4 ml R130 （concentration of 1x10^8 plaque-forming Units/mL,PFU/mL）will be injected intratumoral or intraperitoneal in patients with advanced solid tumors | Drug: Recombinant oncolytic herpes simplex virus type 1 (R130)<br>* R130, a modified herpes simplex virus-Ⅰ (HSV-1) containing the gene coding for anti-CD3 scFv/CD86/PD1/HSV2-US11<br>* Other names: Oncolytic virus;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject incidence of adverse events | To characterize the safety profile of R130 injection in patients with advanced solid tumors as measured by the incidence of Grade ≥ 3 Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) | Up to 6 months | 
| Subject incidence of laboratory abnormalities | Detection of liver and renal function, electrocardiogram, routine blood examination etc. | Up to 1 month | 
| Systemic Immune Response | Detection of increased systemic immune Response markers in sera (IL2,IL4,IL6,IL8,IL10,TNFa，IFNγ, etc.) and peripheral blood mononuclear cells by multi-Color fluorescence-activated cell sorting (FACS) | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Assessment for Disease Control Rate | Evaluate the efficacy endpoints of DCR by the investigator with RECIST v1.1 and iRECIST | Every 10 weeks for 12 months | 
| Disease Assessment for Duration of Response | Evaluate the efficacy endpoints of DOR by the investigator with RECIST v1.1 and iRECIST | Every 10 weeks for 12 months | 
| Quality of Life Assessment | Evaluate with EORTC QLQ-C30 | Every 6 weeks for 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Oncolytic virus, Herpes simplex virus type 1, Immunotherapy