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

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.

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.

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 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 Safety Monitoring Committee (SMC) determined doses.

SGN1 will be administrated in 28-days cycles (once weekly for 3 weeks followed by 1-week rest). Intratumoral injection of SGN1 can be performed directly using methods including but not limited to color doppler ultrasound guidance, which is the preferred method. If the Investigator(s) judge(s) it necessary, the intratumoral injection can also be performed under CT guidance by an interventional radiologist or specialist with adequate qualifications and trainings.

Eligibility Criteria:
Inclusion Criteria:

To be enrolled in the study, patients who have laboratory values outside of the specified ranges will be permitted to be retested. Patients who meet the following criteria at the screening visit will be eligible for participation in the study:

1. Male or female aged 18\~75 years((including 18 and 75 years)) at the time of informed consent;
2. Part 1: Patients with advanced stage (unresectable or metastatic) solid tumors 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 intolerable to standard treatment; Note: For all tumor species included, standard treatment will refer to current Chinese Society of Clinical Oncology (CSCO)/National Comprehensive Cancer Network (NCCN) guidelines.

   Standard treatment failure refers to patients who have disease progression after the existing standard of care recommended by CSCO/NCCN guidelines, or relapse/metastasis after standard of care.

   Non-standard treatment refers to patients who have received the treatment recommended by the guidelines and currently have no other effective treatment options.
3. Part 2: the specific tumor-type expansion study may enroll the following patients: Patients with advanced HNSCC, Sarcoma, HCC, cervical cancer, melanoma, 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.
4. 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 can be injected directly using methods including but not limited to color doppler ultrasound guidance, which is the preferred method. If the Investigator(s) judge(s) it necessary, the intratumoral injection can also be performed under CT guidance 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 and Investigator assessment (no risk of major bleeding or hollow organ perforation).
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
6. Life expectancy ≥ 12 weeks.
7. Patients have recovered from any toxic reaction to previous medications (≤Grade 1 based on NCI-CTCAE v 5.0, except

   1. Hair loss;
   2. Pigmentation;
   3. The long-term toxicity caused by radiotherapy and cannot be recovered by the Investigator's judgment;
   4. Platinum induced neurotoxicity of grade 2 and below;
   5. Hemoglobin at 90 \~ 100 g/L (including boundary value) or stable status assessed by the Investigator.
   6. Patients with adrenal and thyroid dysfunction who maintain a stable state after drug treatment as judged by the Investigator may be included in this study; Patients with toxic reactions of single indicator grade 2 or above that with no clinical significance or clinical treatment measures, which will be determined by the investigator if not affect the study, can also be included.
8. At least one measurable injected lesion as determined by RECIST 1.1(for solid tumors).
9. 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 outside of the specified ranges will be permitted to be retested during the screening period in order to meet the criteria),

   1. Absolute count of neutrophils (ANC) ≥1.5×109/L, platelet ≥75×109/L; Hemoglobin ≥90 g/L;
   2. Serum albumin ≥ 30 g/L; Bilirubin ≤1.5 × ULN, ALT and AST ≤2.5 × ULN;
   3. In patients with liver metastasis, ALT and AST≤5 × ULN;
   4. 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;
   5. International standardized ratio of coagulation function (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (if the patient is taking concomitant anticoagulant medication, whether the coagulation function is qualified will be determined by the Investigator).
10. 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.
11. Female patients of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 6 months after the last dose of drug intratumoral injection.
12. Male patients of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after the last dose of drug intratumoral injection.
13. Patients must be able to follow up after the treatment.
14. Patients must understand and voluntarily sign the informed consent form.

Exclusion Criteria

Patients will be excluded from participation of the study for any of the following criteria:

1. Prior treatment with oncolytic bacteria viral or anti-tumor bacteria therapy.
2. Patients with extremely large tumor (the longest diameter of a single tumor does not exceed 8 cm in principle); patients with multiple lesions cannot receive intratumoral injection, it mainly refers to patients with extensive metastasis who are not suitable for local treatment;
3. Patients who are allergic or intolerant to salmonella sensitive antibiotics, and have infectious diseases and are currently using antibiotics.
4. Present assessable tumors in hollow organs (stomach, esophagus, intestine, urinary tract etc.).
5. 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.
6. Patients who have received the following treatments or drugs before the first treatment with the investigational drug:

   1. Major surgery performed within 28 days before the first treatment with the investigational drug (biopsy is allowed for diagnostic purposes);
   2. Immunosuppressive drugs have been administered within 14 days before the first treatment with the investigational drug (Prednisone \>10 mg/day, or equivalent doses of corticosteroids), 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);
   3. 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; Except for administration of inactivated vaccines and RNA vaccines (e.g., inactivated influenza vaccines and COVID-19 RNA vaccines);
   4. 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).
7. 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.
8. Present with diverticulitis that may cause anaerobic bacteria to multiply or conditions at screening that might promote the unintentional growth of anaerobic bacteria in nontarget lesions.
9. 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);
10. 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);
11. 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.
12. 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;
13. Existing cardiac clinical symptoms or diseases that cannot be well controlled, such as:

    1. NYHA grade 2 or above heart failure;
    2. Unstable angina pectoris;
    3. Myocardial infarction occurred within 1 year;
    4. Patients with supraventricular or ventricular arrhythmias that have clinical significance and need treatment or intervention;
    5. Uncontrolled hypertension (systolic blood pressure) ≥160 mmHg and (diastolic blood pressure) ≥100 mmHg after drug treatment;
    6. Patients with valvular heart disease or mitral valve prolapse, aortic valve disease or other source of turbulent cardiac blood flow.
14. Patients with active or uncontrolled infection or fever \> 38.5°C of unknown cause or before the first administration of the study drug;
15. Documented salmonella infection within 6 months.
16. Known history of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant.
17. Patients participating in other clinical studies or participating in other clinical studies within 4 weeks or 5 half-lives of other study drugs, whichever is longer, prior to enrollment and receiving experimental drug administration.
18. Known history of psychotropic drug abuse or recreational drug abuse;
19. In the judgment of the Investigator, there are other factors that may lead to termination: for example, adrenal cortex insufficiency, pituitary insufficiency after treatment, and 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.
20. Patients with implants such as pacemakers, prosthetic cardiac valves, or vascular stents who require long-term anticoagulant therapy;
21. In the Investigator's judgment, patients who are not suitable for other reasons;
22. Abdominal standing position plain film or abdominal CT indicates the possibility of bowel obstruction within 6 months from screening, or the Investigator believes there is a risk of bowel obstruction.