Study of SGN1 in Patients With Advanced Solid Tumor

Objectives:To assess the safety and tolerability followed by a dose expansion study to characterize safety, and preliminary efficacy of SGN1 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.

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 DLT observation period.

Part 3 is an open-label, dose expansion phase. 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.

In part 3, there will be at least 2 tumor types selected, expand between second to four dose level in each tumor type.The Part 3 (Dose expansion stage study) could be started according to the SMC evaluation, do not need waiting the completion the whole cohort of dose escalation (Part 1).

Eligibility Criteria:
Inclusion Criteria

Patients must meet all the following inclusion criteria:

1. Age 18-75 years inclusive of end value, regardless of gender.
2. 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 intolerant to the standard treatment.

   Part 3: The specific tumor-type expansion study may enroll the following patients: Patients with hepatocellular carcinoma, small cell lung cancer (SCLC), non small cell lung cancer (NSCLC), pancreatic cancer, prostate cancer, bladder cancer, nasopharyngeal carcinoma, sarcoma, melanoma or other tumor type with potential efficacy signal observed in Part 1\&2, who have failed to standard therapy or who are intolerant to the standard treatment. There will be 2-4 cohorts of dose expansion in specified tumor types.

   Note: For all tumor species included, standard treatment will refer to current CSCO/NCCN guidelines.

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

   Nonstandard treatment refers to patients who have received the treatment recommended by the guidelines and currently have no other effective treatment options.
3. 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.
4. At least 1 measurable lesion according to RECIST 1.1 (for solid tumors).
5. 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.
6. Eastern Co-Operative Oncology Group (ECOG) performance status 0 \~ 1 and a life expectancy of at least 3 months.
7. 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 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 ≥30g /L; Bilirubin ≤1.5 × Upper Limit of Normal (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 patient has concomitant medication with anticoagulants, whether the coagulation function is qualified will be determined by Investigator.)
8. 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.
9. Female patients of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 6 months after last dose of drug infusion.
10. Male patients of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after last dose of drug infusion.
11. 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.
12. Patients must be able to follow up after the treatment.
13. Patients must understand and voluntarily sign the informed consent form.

Exclusion Criteria

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

1. Received systemic or absorbable dosage of steroid hormone (prednisone or equivalent) of \> 10 mg/day in the 14 days prior to enrollment;

   1. Prednisone \> 10 mg/day
   2. Dexamethasone \> 1.5 mg/day.
2. Allergic or intolerant to salmonella sensitive antibiotics, or combined with infectious diseases and currently using antibiotics.
3. Present assessable tumors in hollow organs (Stomach, esophagus, intestine, urinary tract etc.).
4. Present with symptomatic central nervous system metastasis or brain abscess at screening.
5. Present with diverticulitis or conditions at screening that might promote the unintentional growth of anaerobic bacteria in non target lesions.
6. 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.
7. 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).
8. 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).
9. 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.
10. Patients with Anti-TP positive.
11. 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.
12. 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).
13. Received live or attenuated vaccines within 4 weeks of study drug administration, during treatment, or within 5 months of the last administration.
14. 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 14.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.
15. In the researcher's judgment, patients who are not suitable for other reasons.
16. Documented salmonella infections within 6 months.
17. 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.
18. Patients with implants such as pacemakers, prosthetic cardiac valves, or metal orthopedic prostheses (not include vascular implants for Part 3).