Study of SGN1 in Patients With Advanced Solid Tumor

Study Overview
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Brief Summary
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Objectives:To assess the safety and tolerability followed by a dose expansion study to characterize safety, and preliminary efficacy of SGN1, a genetically modified strain of Salmonella enterica, serotype typhimurium that expresses L-Methioninase,in participants with refractory solid tumors. 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:The treatment populations shall be 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
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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/IIa clinical trial with 3 parts: Part 1 & 2 is an open-label, dose escalation phase. Part 1 is the DLT observation period, and the patients will enter part 2 for extension treatment after completing the 28-day DLT observation period. In part 1& 2 of the study will employ a standard 3 + 3 escalating dose design to explore dose limiting toxicities (DLTs) in sequential cohorts to select the maximum tolerated dose (MTD). In part 2, the treatment may be terminated if the patients withdraws, has unacceptable toxicity, develops disease progression, experiences an AE that cannot be resolved with/without rescue medication and cause stopping study drug for 2 planned administrations, death, or loss to follow-up. In such cases, patients will be discontinued and palliative or rescue therapy will be offered to those that terminate early.

Official Title
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Phase I/IIa, Open-label Study to Evaluate Safety, Tolerability and Preliminary Efficacy of Modified Salmonella Typhimurium SGN1 in Patients With Advanced Solid Tumor

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: SGN1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet all the following inclusion criteria: Age 18-75 years inclusive of end value, regardless of gender. 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 3: Patients who meet all the standards above and should be the selected tumor type according to part1&2. Patients finished anti-tumor therapy including chemotherapy, immunotherapy, biological agents, hormone therapy, radiotherapy (except local radiotherapy for pain relief) ≥ 4 weeks prior to the first dose of study drug. At least 1 measurable lesion according to RECIST 1.1 (for solid tumors). Patients have recovered from any toxic reaction to previous medications (≤Grade 1 based on NCI-CTCAE v 5.0, except a. Hair loss; b. Pigmentation; c. The long-term toxicity caused by radiotherapy and cannot be recovered by the investigator's judgment; d. Platinum induced neurotoxicity of grade 2 and below; e. Hemoglobin at 90   100 g / L (including boundary value)) or stable status assessed by the investigator. Eastern Co-Operative Oncology Group (ECOG) performance status 0   1 and a life expectancy of at least 3 months. Laboratory tests must meet the following requirements and have not received any blood cell growth factor 14 days before the test (Patients with laboratory values outside of the specified ranges will be permitted to be retested once in order to meet the criteria), rescreening for Hemoglobin, ALT, AST and coagulation function is allowed but only allowed once: 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 infusion. Male patients of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after drug infusion Patients with chronic HBV infection with active disease who meet the criteria for anti HBV therapy (HBV DNA test is less than 2000 IU/ml) should be on a suppressive antiviral therapy prior to initiation of cancer therapy. Patients with a history of HCV infection should have completed curative antiviral treatment and HCV viral load below the limit of quantification. Patients with HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible. Patients on concurrent HCV treatment should have HCV below the limit of quantification. Patients must be able to follow up after the treatment. Patients must understand and voluntarily sign the informed consent form. Exclusion Criteria: Patients will be excluded from participation for any of the following criteria: Received systemic or absorbable dosage of steroid hormone (prednisone or equivalent) of >10 mg/day in the 14 days prior to enrollment; Prednisone >10 mg/day Dexamethasone >1.5 mg/day. Currently using antibiotic. Tumors in hollow organs (Stomach, esophagus, intestine, urinary tract etc.). Present with symptomatic central nervous system metastasis or brain abscess at screening. Present with diverticulitis or conditions at screening that might promote the unintentional growth of anaerobic bacteria in nontarget lesions. Existing cardiac clinical symptoms or diseases that cannot be well controlled, 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. Those who had received radiotherapy, chemotherapy, hormone therapy, surgery or molecular targeted therapy that ended fewer than 4 weeks before the first dose of study treatment (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 active or uncontrolled infection or fever, >38.5℃, of unknown cause during screening or before the first administration of the study drug (according to the judgment of the researcher, fever caused by tumor can be included). Positive for the presence of human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2) (positive antigen/antibody and nucleic acid tests); or follow standard of care for HIV diagnosis. Patients with Anti-TP positive. 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. 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) ; Received live or attenuated vaccines within 4 weeks of study drug administration, during treatment, or within 5 months of the last administration. 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. In the researcher's judgment, patients who are not suitable for other reasons. Documented salmonella infections within 6 months. Allergic to any study medications or rescue medications. Patients with implants such as pacemakers, prosthetic cardiac valves, or metal orthopedic prostheses.

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
Interventional Model Description: The study will employ a standard 3 + 3 escalating dose design to explore dose limiting toxicities (DLTs). Currently plans to evaluate 5 cohorts with 3- 6 patients to determine the Maximum Tolerated Dose (MTD). Patients who had no dose-limiting toxicities observed in Part 1 proceeded to Part 2. Alternatively, if a DLT occurs in only 1/3 patients at any dose, then the SMC will review the data and determine if 3 more patients should be enrolled at this dose level. If this is the highest dose and there have been no DLTs-then 3 more patients must be evaluated at the same dose level to confirm the MTD. The MTD is defined as the highest dose at which no more than one (1) DLT is observed among 6 patients. Part 3 is an open-label study designed to adopt the optimal biologic dose in no more than 2 specific tumor subtypes. The tumor types will be selected based on safety and preliminary efficacy evaluated in Part 1&2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort<br>Cohorts of 3 patients will be enrolled. The first patient of each cohort in Part 1 will be admitted to an infusion unit and treated with an IV infusion of SGN1 over 2 hours. All dosed patients will be closely evaluated for DLTs for 28 days post first dose. Up to 5 cohorts will be evaluated. Part 3 is an open-label study designed to adopt the optimal biologic dose in no more than 2 specific tumor subtypes. The tumor types will be selected based on safety and preliminary efficacy evaluated in Part 1&2. | Drug: SGN1<br>* SGN1, will be administered as an IV infusion, via an IV catheter over 2 hours, which unit dose strength is 0.9-2.0×109 cfu /vial.<br>* Other names: SalMet-Vec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of AEs (adverse events). | An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. 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 Inpatient 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. | 
| Progress 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 subject is suspected to have 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 with any dose limiting toxicity (DLT),to determine the MTD. | Any of the following judged to be associated with SGN1 (i.e., possibly-, probably-, or definitely related to), 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 or ALT that is associated with a Grade 2 or greater rise in bilirubin. | Up to 28 days post first dose. | 
| Incidence with adverse events and preliminary efficacy data to determine the OBD. | OBD will be determined by adverse events, preliminary efficacy data,and the OBD determined by the SMC. | From receiving study drug and throughout the study, until 28 days after the last dosing. | 
| PK analysis of SGN1 level in blood. | Concentrations of SGN1 will be measured. In Part 1, blood sampling for pharmacokinetics will be conducted for pharmacokinetics (PK) during the first dose. | Pre-dose,30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 2 hours 20 minutes, 2 hours 40 minutes, 3 hours, 3 hours 30 minutes, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours after the start first dose. | 
| Bacterial shedding of SGN1 level in blood. | Blood samples for both PK and bacterial shedding will be collected and processed in the same manner for the first SGN1 administration. For subsequent SGN1 infusions (starting with Dose 2), blood samples shall be collected within 2 hours prior to the start of SGN1 infusion and within 24 hours of end of infusion. If blood samples test positive for SGN1, collection of shedding samples should continue with weekly SGN1 administration until the samples from three consecutive infusions 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. | 
| Bacterial shedding of SGN1 level in urine. | For the first SGN1 administration (C1D1), urine sampling for bacterial shedding will be conducted. For subsequent SGN1 infusions (starting with Dose 2), urine samples shall be collected within 2 hours prior to the start of SGN1 infusion and within 24 hours of end of infusion. If urine samples test positive for SGN1, collection of shedding samples should continue with weekly SGN1 administration until the samples from three consecutive infusions 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. | 
| Bacterial shedding of SGN1 level in saliva. | For the first SGN1 administration (C1D1), saliva sampling for bacterial shedding will be conducted. For subsequent SGN1 infusions (starting with Dose 2), saliva samples shall be collected within 2 hours prior to the start of SGN1 infusion and within 24 hours of end of infusion. If saliva samples test positive for SGN1, collection of shedding samples should continue with weekly SGN1 administration until the samples from three consecutive infusions 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. | 
| Bacterial shedding of SGN1 level in feces. | For the first SGN1 administration (C1D1), feces sampling for bacterial shedding will be conducted. For subsequent SGN1 infusions (starting with Dose 2), will be collected by the subject within 24 hours prior to infusion and within 24 hours after the end of infusion. If feces samples test positive for SGN1, collection of shedding samples should continue with weekly SGN1 administration until the samples from three consecutive infusions result below the limit of detection (LOD). In EOT/ET visit, feces samples will be collected by the patient within 24 hours prior to the EOT/ET visit. | Before the first administration up to 28 days after the last dosing. | 
| Assessment of tumor colonization. | For appropriate superficial tumors, colonization of the tumor by SGN1 will be assessed by fine needle aspiration and/or excise biopsies every 8 weeks. | From receiving study drug and throughout the study, until 28 days after the last dosing. | 
| Proinflammatory cytokines | Proinflammatory cytokines including IL-1β, IFN-γ,TNF-α, IL-6, and IL-8. | Within 7 days prior to the first dose, and at 2, 4, 6, and 24 hours post end of first infusion. |