Study of SGN1 Administered Via Intratumoral Injection in Patients With Advanced Solid Tumor

Study Overview
=================
Brief Summary
-----------------
Objectives: To characterize safety, tolerability, MTD and OBD of intratumoral injection of SGN1 in patients with advanced solid tumors, and to preliminarily investigate the efficacy and safety of SGN1 in specific tumor subtypes at OBD doses. Study Rationale: The mechanism of action for SGN1 is based on the fact that most tumors are methionine dependent. SGN1 is designed to be used as a tumor therapeutic bacterium that can preferentially replicate and accumulate in tumors and starve them of essential amino acids by delivering the oncolytic enzyme L-Methioninase. Patient Population: Patients presenting with histologically confirmed advanced and/or metastatic solid tumors that are refractory to standard therapy and for which no other conventional therapy exists.

Detailed Description
-----------------
Methionine starvation can powerfully modulate DNA methylation, cell cycle transition, polyamines and antioxidant synthesis of tumor cells, in contrast to normal ones. L-Methioninase is a pyridoxal phosphate dependent enzyme that catalyzes the γ-elimination reaction of L-methionine to methanethiol, α-ketobutyrate and ammonia . Absolute-dependency on exogenous supply of L-methionine, not homocysteine, for growth and proliferation of tumors is the pivotal biochemical criterion for various human cancers. SGN1 is a genetically modified strain of Salmonella enterica, serotype typhimurium that expresses L-Methioninase. The attenuated live bacterium has been investigated in China for utility in treating advanced solid tumors. The mechanism of action for SGN1 is based on the fact that most tumors are methionine dependent. SGN1 is designed to be used as a tumor therapeutic bacterium that can preferentially replicate and accumulate in tumors and starve them of essential amino acids by delivering the oncolytic enzyme L-Methioninase. This study is a multi-center phase I clinical trial with 2 parts: Part 1 is a phase I open-label, dose escalation study phase. The purpose of Part 1 is to characterize safety, tolerability, MTD and OBD of intratumoral injection of SGN1 in patients with advanced solid tumors. Part 2 is as a part of a phase Ib/IIa study, which is a specific Tumor-type expansion study, the purpose of Part 2 is to preliminarily investigate the efficacy and safety of SGN1 in specific tumor subtypes at OBD doses. SGN1 will be administrated in 28-days cycles (once weekly for 3 weeks followed by 1-week rest). Intratumoral injection of SGN1 could be performed under color doppler ultrasound guidance and by an interventional radiologist or specialist with adequate qualifications and trainings.

Official Title
-----------------
A Phase I/IIa, Open-label, Dose Escalation and Dose-Expansion Study to Evaluate the Safety and Tolerability of Modified Salmonella Typhimurium SGN1 Administered Via Intratumoral Injection in Patients With Advanced Solid Tumors

Conditions
-----------------
Advanced Solid Tumor

Intervention / Treatment
-----------------
* Drug: SGN1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female aged 18 75 years at the time of informed consent. Part 1: Patients with advanced stage (unresectable or metastatic) cancer including but not limited to small cell lung cancer, non-small cell lung cancer (adeno- and squamous), Hodgkin's lymphoma or non-Hodgkin's lymphoma, sarcoma, cervical carcinoma, Melanoma, head and neck cancer, breast cancer, ovarian cancer, pseudomyxoma peritoneum (Pseudomyxoma peritonei, PMP) and hepatocellular carcinoma characterized by failure of standard treatment (disease progression or intolerance, such as chemotherapy, targeted therapy, and other immunotherapies) or patients who have no standard treatment or patients who are unable to receive standard treatment. Part 2: the specific tumor-type expansion study may enroll the following patients: Patients with HNSCC, Sarcoma, or other tumor type with potential efficacy signal observed in Part 1, who have failed to standard therapy or who are intolerant to the standard treatment. Patients must have the main lesion suitable for local injection of SGN1. The tumors must be in situ or metastatic solid tumors that are subcutaneous, palpable, or could be injected directly under color doppler ultrasound guidance and by an interventional radiologist or specialist with adequate qualifications and trainings, provided that these tumors do not invade the walls of blood vessels or hollow organs confirmed by previous imaging studies. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1. Life expectancy ≥ 12 weeks. Patients have recovered from any toxic reaction to previous medications (≤Grade 1 based on NCI-CTCAE v 5.0, except Hair loss; Pigmentation; The long-term toxicity caused by radiotherapy and cannot be recovered by the investigator's judgment; Platinum induced neurotoxicity of grade 2 and below; Hemoglobin at 90   100 g / L (including boundary value) or stable status assessed by the investigator. At least one measurable lesion as determined by RECIST 1.1(for solid tumors). Laboratory tests must meet the following requirements and have not received any blood cell growth factor 14 days before the test and no blood transfusions within 14 days prior to screening (patients with laboratory values (hemoglobin, ALT, AST and coagulation function) outside of the specified ranges will be permitted to be retested once during the screening period in order to meet the criteria), Absolute count of neutrophils (ANC) ≥1.5×109 /L, platelet ≥75×109 /L; Hemoglobin ≥90 g/L; Serum albumin ≥ 25g /L; Bilirubin ≤1.5 × ULN, ALT and AST ≤2.5 × ULN; In patients with liver metastasis, ALT and AST≤5 × ULN; Creatinine clearance ≥50 mL/min (standard Cockcroft -Gault formula) or Cr ≤1.5 ×ULN: urinary protein ≤2+ or urinary protein quantitative <1.0 g/L; International standardized ratio of coagulation function (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN. If female, be either postmenopausal for at least 1 year with documented follicle stimulating hormone (FSH) >30 IU/L, or surgically sterile for at least 3 months, or if a woman of childbearing potential, must be non-pregnant confirmed by blood and urine pregnancy tests, and non-lactating. Female patients of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 6 months after drug intratumoral injection. Male patients of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after drug intratumoral injection. Patients must be able to follow up after the treatment. Patients must understand and voluntarily sign the informed consent form. Exclusion Criteria: Prior treatment with oncolytic bacteria. Patients with extremely large tumor (the longest diameter of a single tumor exceeds 8 cm). Currently using antibiotic. Tumors in hollow organs (stomach, esophagus, intestine, urinary tract etc.). Patients who are known to be allergic to the investigational drug or any of its excipients; or rescue medications; or have a severe allergic reaction to other monoclonal antibodies. Patients who have received the following treatments or drugs before the first treatment with the investigational drug: Major surgery performed within 28 days before the first treatment with the investigational drug (biopsy is allowed for diagnostic purposes); Immunosuppressive drugs have been administered within 14 days before the first treatment with the investigational drug (Prednisone >10 mg/day, Dexamethasone >1.5 mg/day), excluding corticosteroid nasal sprays and inhaled corticosteroids or physiological doses of systemic steroid hormones (i.e., prednisone not exceeding 10 mg/d or equivalent physiological doses of other corticosteroids); Inoculation of (attenuated) live virus vaccine: within 28 days before the first dosing of study drug, or during the study period or 60 days after the last dose of study drug; Any anti-tumor therapies (including chemotherapy, radiotherapy, immunotherapy, endocrine therapy, targeted therapy, biological therapy or tumor embolization) within 28 days before the first dosing of the investigational drug (if nitrosourea or mitomycin chemotherapy the interval between end of chemotherapy and first dose of study treatment must be no less than 6 weeks). Patients with known uncontrollable or symptomatic active CNS metastases, manifested by clinical symptoms, brain edema, spinal cord compression, cancerous meningitis, leptomeningeal disease, and/or progressive growth. patients with a history of metastases to the central nervous system or spinal cord compression can be included in the study if they have clearly received treatment and have shown stable clinical manifestations after the discontinuation of anticonvulsants and steroids for 4 weeks before the first dose of the investigational drug. Present with diverticulitis or conditions at screening that might promote the unintentional growth of anaerobic bacteria in nontarget lesions. Symptomatic, advanced patients whose tumors have spread to the internal organs and are at risk of life-threatening complications in the short term (including patients with uncontrollable large amounts of effusion (thoracic cavity, pericardial cavity, or abdominal cavity); Patients with any active autoimmune diseases or a history of any autoimmune disease with predictable recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [only patients whose condition can be controlled by hormone replacement therapy can be included]; Patients with skin diseases that do not require systemic treatment such as vitiligo, psoriasis, hair loss, Type I diabetes mellitus, or those with childhood asthma which has been completely relieved and requires no interventions in adulthood, can be included. Those with asthma who need bronchodilators for medical intervention cannot be included); Patients with other active malignant tumor(s) within 2 years before entering the study. Patients with history of cervical carcinoma in situ, superficial or non-invasive bladder cancer or basal cell or squamous cell cancer in situ previously treated with curative intent may be included at the judgment of the Investigator. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis (hepatitis B, defined as: hepatitis B virus surface antigen [HBsAg] testing positive, HBV-DNA ≥ 500 IU/ml and abnormal liver function; hepatitis C, defined as: hepatitis C antibody [HCV-Ab] testing positive, higher HCV-RNA than the lower limit of detection of the analysis method and abnormal liver function) or hepatitis B and hepatitis C co-infection; Existing cardiac clinical symptoms or diseases that cannot be wellcontrolled, such as: NYHA grade 2 or above heart failure; Unstable angina pectoris; Myocardial infarction occurred within 1 year; Patients with supraventricular or ventricular arrhythmias that have clinical significance and need treatment or intervention; Uncontrolled hypertension (systolic blood pressure) ≥160 mmHg and (diastolic blood pressure) ≥100 mmHg after drug treatment; Patients with valvular heart disease or mitral valve prolapse, aortic valve disease or other source of turbulent cardiac blood flow. Patients with active or uncontrolled infection or fever > 38.5°C of unknown cause or before the first administration of the study drug (according to the judgment of the researcher, fever caused by tumor can be included); Diverticulitis that may cause anaerobic bacteria to multiply. Documented salmonella infection within 6 months. Known history of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant. Patients participating in other clinical studies or participating in other clinical studies within 4 weeks (or 5 half-lives of other study drugs) prior to enrollment and receiving experimental drug administration. Known history of psychotropic drug abuse or recreational drug abuse; In the judgment of the investigator, there are other factors that may lead to termination: for example, other serious diseases (including mental diseases) need to be treated together, there are serious abnormalities in laboratory examination, family or social factors, which may affect the safety of the patients or test data and sample collection. Vaccination within 28 days of the first trial treatment, except for administration of inactivated vaccines and RNA vaccines (e.g., inactivated influenza vaccines and COVID-19 RNA vaccines); Patients with implants such as pacemakers, prosthetic cardiac valves, or metal orthopedic prostheses. In the investigator 's judgment, patients who are not suitable for other reasons.

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
Interventional Model Description: This study will be conducted in 2 parts: Part 1 is a phase I open-label, dose escalation study phase. Part 2 is as a part of a phase Ib/IIa study, which is a specific Tumor-type expansion study. The standard 3+3 dose escalation algorithm will be applied to explore dose limiting toxicity (DLTs) in up to 5 sequential cohorts with 3- 6 patients and identify the maximally tolerated dose (MTD). When the cohort is completed in Part 1, the Part 2 study could be started according to the SMC evaluation (If there is no DLT, and there is the complete response [CR] or partial response [PR] observed at the cohort or at least all patients have stable disease [SD] result available for the tumor assessment).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cohort<br>The standard 3+3 dose escalation algorithm will be applied to explore dose limiting toxicity (DLTs) in up to 5 sequential cohorts with 3- 6 patients and identify the maximally tolerated dose (MTD). When the cohort is completed in Part 1, the Part 2 study could be started according to the SMC evaluation (If there is no DLT, and there is the complete response [CR] or partial response [PR] observed at the cohort or at least all patients have stable disease [SD] result available for the tumor assessment). | Drug: SGN1<br>* SGN1,will be administered intratumorally,which dosage is 0.9-2.0×109 cfu /vial.<br>* Other names: SalMet-Vec;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | An AE is any untoward medical occurrence in a patient or clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Events meeting the definition of an AE include: Any abnormal laboratory test results (hematology, serum chemistry, or urinalysis) or other safety assessments (e.g., ECGs, vital signs measurements), including those that worsen from baseline, and was felt to be clinically significant in the medical and scientific judgment of the Investigator. Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study. Signs, symptoms, or the clinical sequelae of a suspected interaction. | From receiving study drug and throughout the study, until 28 days after the last dosing | 
| Incidence of SAEs | An AE or suspected adverse reaction is considered serious if it results in any of the following outcomes: Death Life-threatening In patient hospitalization or prolongation of existing hospitalization A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. | From receiving study drug and throughout the study, until 28 days after the last dosing | 
| Objective response rate (ORR) | The efficacy endpoints include ORR, DCR and PFS. • The ORR is defined as the proportion of patients who achieve PR or better according to the RECIST v1.1. mRECIST is used to assess Hepatocellular carcinoma, and LYRIC is used to assess Lymphoma as assessed by investigator | From signing the informed consent form until 28 days after the last dose. | 
| Disease control rate (DCR) | The efficacy endpoints include ORR, DCR and PFS. • The DCR is defined as the proportion of patients who achieve SD or better according to the RECIST v1.1, mRECIST is used to assess Hepatocellular carcinoma, and LYRIC is used to assess Lymphoma as assessed by investigator. | From signing the informed consent form until 28 days after the last dose. | 
| Progression Free Survival (PFS) | The efficacy endpoints include ORR, DCR and PFS. • PFS is defined as the time interval from date of first dose of SGN1 to the date of documented disease progression (iRECIST is used when the patient is suspected to be pseudo disease progression) or death due to any cause, whichever occurs first. | From signing the informed consent form until 28 days after the last dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicity (DLTs) | Any of the following judged to be associated with SGN1 may be considered a DLT: Any Grade 5 adverse event that is at least possibly related to investigational drug Grade 4 non-hematological toxicities (excluding alopecia) of any duration Grade 3 non-hematologic (non-laboratory) toxicity lasting at least 7 days despite optimal supportive care Any Grade 3 non-hematologic laboratory value if: a) medical intervention is required to treat the patient; or b) the abnormality leads to hospitalization; or c) the abnormality persists for at least 7 days Grade 4 hematologic toxicity, other than those specified in criteria 6 and 7 below, lasting longer than 7 days Grade 3 or Grade 4 febrile neutropenia of any duration Grade 3 thrombocytopenia in combination with a Grade 3 or greater blood and lymphatic system disorder Grade 3 AST (Aspartate Aminotransferase) or ALT (Alanine Aminotransferase) that is associate | Upon completion of the 28-day observation periods in the cohort. | 
| SGN1 level in blood for PK analysis | In Part 1, blood will be collected to analyze and describe the PK of SGN1. | Pre-dose of first injection, 10minutes,0.5hours,1hour,1.5hours,2hours,4hours,6hours,8hours,24hours,48hours,72hours after the end of first dose | 
| SGN1 level in blood for bacterial shedding. | Blood samples for both PK and bacterial shedding will be collected and processed in the same manner for the first SGN1 administration (C1D1). For subsequent SGN1 intratumoral injections (starting with Dose 2),blood samples shall be collected. If blood samples test positive for SGN1, collection of shedding samples should continue with SGN1 intratumoral injection until the samples from three consecutive intratumoral injections result below the limit of detection (LOD). In EOT/ET visit, blood samples for bacterial shedding will be collected. | Before the first administration up to 28 days after the last dosing. | 
| SGN1 level in urine for bacterial shedding. | For the first SGN1 administration (C1D1), urine sampling for bacterial shedding will be conducted. For subsequent SGN1 intratumoral injections (starting with Dose 2), urine samples shall be collected. If urine samples test positive for SGN1, collection of shedding samples should continue with SGN1 intratumoral injection until the samples from three consecutive intratumoral injections result below the limit of detection (LOD). In EOT/ET visit, urine samples for bacterial shedding will be collected. | Before the first administration up to 28 days after the last dosing. | 
| SGN1 level in saliva for bacterial shedding. | For the first SGN1 administration (C1D1), saliva sampling for bacterial shedding will be conducted. For subsequent SGN1 intratumoral injections (starting with Dose 2), saliva samples shall be collected. If saliva samples test positive for SGN1, collection of shedding samples should continue with SGN1 intratumoral injection until the samples from three consecutive intratumoral injections result below the limit of detection (LOD). In EOT/ET visit, saliva samples for bacterial shedding will be collected. | Before the first administration up to 28 days after the last dosing. | 
| SGN1 level in feces for bacterial shedding. | TFor the first SGN1 administration (C1D1), feces sampling for bacterial shedding will be conducted. For subsequent SGN1 intratumoral injections (starting with Dose 2), feces samples shall be collected. If feces samples test positive for SGN1, collection of shedding samples should continue with SGN1 intratumoral injection until the samples from three consecutive intratumoral injections result below the limit of detection (LOD). feces samples will be collected by the subject within 24 hours prior to the EOT/ET visit. | Before the first administration up to 28 days after the last dosing. | 
| Proinflammatory cytokines | Blood samples will be collected to assess proinflammatory cytokines including IL-1β, IFN-γ, TNF-α, IL-6 and IL-8. | Within 7 days prior to first dosing, and at 2, 4, 6, and 24 hours post end of first infusion. | 
| Assessment of tumor colonization | For superficial tumors, colonization of the tumor by SGN1 will be assessed by fine needle aspiration (FNA) every 8 weeks(±7days). | From receiving study drug and throughout the study, until 28 days after the last dosing |