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

Advanced Solid Tumor Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05103345
• Other study ID #: SGN-P01-002
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 19, 2023
• Est. completion date: June 30, 2028

Study information

• Verified date: February 2024
• Source: Guangzhou Sinogen Pharmaceutical Co., Ltd
• Contact: Garin Liu
• Phone: +886-(0) 905 891 942
• Email: Garin.Liu[@]parexel.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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/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 tumor can also be injected under CT guidance by an interventional radiologist or specialist with adequate qualifications and trainings.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: June 30, 2028
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Male or female aged 18~75 years at the time of informed consent;

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 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 tumor can also be injected 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. If there is liquefaction inside the tumor judged by the Investigator during treatment, it is recommended to use ultrasound to check the internal liquefaction of the tumor.

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.

8. At least one measurable 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.

2. Patients with extremely large tumor (the longest diameter of a single tumor exceeds 8 cm); 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, 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);

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;

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 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 (according to the judgment of the researcher, fever caused by tumor can be included);

15. Diverticulitis that may cause anaerobic bacteria to multiply.

16. Documented salmonella infection within 6 months.

17. Known history of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant.

18. 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.

19. Known history of psychotropic drug abuse or recreational drug abuse;

20. 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.

21. 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);

22. Patients with implants such as pacemakers, prosthetic cardiac valves, or metal orthopedic prostheses (this does not include vascular implants for Part 2);

23. In the Investigator's judgment, patients who are not suitable for other reasons;

24. 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.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Neoplasms

Intervention

Drug:
• SGN1
SGN1,will be administered intratumorally,which dosage is 0.9-2.0×109 cfu /vial.

Locations

Country	Name	City	State
China	West China Hospital of Sichuan University	Chengdu	Sichuan
Taiwan	Taipei Medical University-Shuang Ho Hospital,Ministry of Health and Welfare	New Taipei
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taipei Municipal Wan Fang Hospital	Taipei City

Sponsors (2)

Lead Sponsor	Collaborator
Guangzhou Sinogen Pharmaceutical Co., Ltd	Parexel

Countries where clinical trial is conducted

China,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Tumor biomarkers upon tumor types	The changes before and after treatment of tumor biomarkers upon tumor types.	From signing the informed consent form until 28 days after the last dose.
Primary	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
Primary	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
Primary	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 only, Choi criteria is used for all solid tumors, during the whole study, as the only exploratory tumor assessment method in the study, and LYRIC is used to assess Lymphoma as assessed by the investigator.	From signing the informed consent form until 28 days after the last dose.
Primary	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 only, Choi criteria is used for all solid tumors, during the whole study, as the only exploratory tumor assessment method in the study, and LYRIC is used to assess Lymphoma as assessed by the investigator.	From signing the informed consent form until 28 days after the last dose.
Primary	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	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; Non-hematological toxicities: Grade 4 non-hematological toxicities (excluding alopecia) lasting > 3 days despite optimal supportive care (OSC).; Grade 3 non-hematologic toxicities lasting > 7 days despite OSC.; Hematological toxicities: Grade 4 hematologic toxicities lasting > 7 days (except following b and c).; Grade 3 or 4 febrile neutropenia (body temperature =38.5°C) lasting > 7 days.; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia.	Up to 28 days post first dose
Secondary	SGN1 level in blood for PK analysis	In Part 1 and Part 2, blood sampling will be collected for pharmacokinetics (PK).; The blood collection times for PK are within 30 minutes predose and 30 minutes postdose of intratumoral injection on C1D1(cycle1 day1), C1D8(cycle1 day8), C1D15(cycle1 day15), C2D1(cycle2 day1), C2D8(cycle2 day8), and C2D15(cycle2 day15), and at the following timepoints after the end of dose on C1D1 and C2D1: 5 minutes (± 1 minute), 10 minutes (± 1 minute), 0.5 hour (± 2 minutes), 1 hour (± 2 minutes), 1.5 hours (± 2 minutes), 2 hours (± 2 minutes), 4 hours (± 5 minutes), 6 hours (± 10 minutes), 8 hours (± 15 minutes), 24 hours ± 1 hour, 48 hours ± 1 hour, 72 hours ± 1 hour. If there are still symptoms of fever or infection after 72 hours, extend the PK collection time and expect to increase it every 24 hours until the infection symptoms disappear.	Before and after SGN1 injection in the first two cycles in Part 1 and Part 2.
Secondary	SGN1 level in blood for bacterial shedding.	In Part 1 and Part 2,blood samples will be collected for Bacterial Shedding.; Blood samples will be collected within 2 hours prior to the start of SGN1 intratumoral injection on C1D8 and C1D15, and within 24±3 hours after the end of each SGN1 intratumoral injection on C1D8 and C1D15.; Blood bacterial samples within 30 minutes predose and 30 minutes postdose of intratumoral injection on C1D1, C1D8, C1D15, C2D1, C2D8, and C2D15 are measured in the PK analysis described above. The results from PK blood samples will contribute to the analysis as the bacterial shedding.; In EOT/ET visit, blood samples for bacterial shedding will be collected.	Before the first administration up to 28 days after the last dosing.
Secondary	SGN1 level in urine for bacterial shedding.	In Part 1 and Part 2, urine samples will be collected for Bacterial Shedding.; For the first SGN1 administration (C1D1), urine sampling will be conducted within 2 hours before intratumoral injection, 3 hours ±1 hour, 6 hours ±1 hour, 24 hours ±3 hours, 48 hours ±3 hours and 72 hours ±3 hours after end of intratumoral injection.; For the second and third administration(C1D8 and C1D15),urine samples for bacterial shedding will be collected within 2 hours prior to the start of SGN1 intratumoral injection, and within 24 ± 3 hours after the end of each SGN1 intratumoral injection.; In EOT/ET visit, urine samples for bacterial shedding will be collected.	Before the first administration up to 28 days after the last dosing.
Secondary	SGN1 level in saliva for bacterial shedding.	In Part 1 and Part 2, saliva samples will be collected for Bacterial Shedding.; For the first SGN1 administration (C1D1), saliva sampling will be conducted within 2 hours before intratumoral injection, 3 hours ±1 hour, 6 hours ±1 hour, 24 hours ±3 hours, 48 hours ±3 hours and 72 hours ±3 hours after end of intratumoral injection.; For the second and third administration(C1D8 and C1D15),saliva samples for bacterial shedding will be collected within 2 hours prior to the start of SGN1 intratumoral injection, and within 24 ± 3 hours after the end of each SGN1 intratumoral injection.; In EOT/ET visit, saliva samples for bacterial shedding will be collected.	Before the first administration up to 28 days after the last dosing.
Secondary	SGN1 level in feces for bacterial shedding.	In Part 1 and Part 2, feces samples will be collected for Bacterial Shedding.; For the first SGN1 administration (C1D1), feces sampling for bacterial shedding will be collected by the patient before the intratumoral injection of SGN1,this sample may be collected at any time during the screening period. Additional feces samples will be collected after the end of the intratumoral injection on C1D1 within the time frames below: 0-24 hours 24-48 hours 48-72 hours; For the second and third administration(C1D8 and C1D15),feces samples for bacterial shedding will be collected by the patient within 24 hours prior to the start of each SGN1 intratumoral injection, and within 24 hours after the end of each SGN1 intratumoral injection.; In EOT/ET visit, 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.
Secondary	Proinflammatory cytokines	Blood samples will be collected to assess proinflammatory cytokines including IL-1ß, IFN-?, TNF-a, 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.
Secondary	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