Phase I/IIa, Open-label Study to Evaluate Safety, Tolerability and Preliminary Efficacy of Modified Salmonella Typhimurium SGN1 in Patients With Advanced Solid Tumor
Overview
- Phase
- Phase 1
- Intervention
- SGN1
- Conditions
- Advanced Solid Tumor
- Sponsor
- Guangzhou Sinogen Pharmaceutical Co., Ltd
- Enrollment
- 70
- Locations
- 8
- Primary Endpoint
- Objective response rate (ORR)
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
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.
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/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).
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Cohort
In part 1\&2, 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. Patients in Part 1 will enter Part 2 for extension treatment after completing the 28-day DLT observation period. Up to 5 cohorts will be evaluated. Part 3 is an open-label, dose expansion phase.There will be at least 2 tumor types selected, expand between second to four dose level in each tumor type .
Intervention: SGN1
Outcomes
Primary Outcomes
Objective response rate (ORR)
Time Frame: From signing the informed consent form until 28 days after the last dose.
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 and Choi, mRECIST is used to assess Hepatocellular carcinoma, and LYRIC is used to assess Lymphoma. as assessed by investigator.
Incidence of SAEs.
Time Frame: From receiving study drug and throughout the study, until 28 days after the last dosing.
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.
Incidence and severity of AEs (adverse events).
Time Frame: From receiving study drug and throughout the study, until 28 days after the last dosing.
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.
Disease control rate (DCR)
Time Frame: From signing the informed consent form until 28 days after the last dose.
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 and Choi , mRECIST is used to assess Hepatocellular carcinoma, and LYRIC is used to assess Lymphoma. as assessed by investigator.
Progress Free Survival (PFS)
Time Frame: From signing the informed consent form until 28 days after the last dose.
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.
Secondary Outcomes
- Bacterial shedding of SGN1 level in feces.(Before the first administration up to 28 days after the last dosing.)
- Anti-Drug antibody (ADA) of SGN1.(Before the first administration up to 28 days after the last dosing.)
- Incidence with any dose limiting toxicity (DLT),to determine the MTD.(Up to 28 days post first dose.)
- Incidence with adverse events and preliminary efficacy data to determine the OBD.(From receiving study drug and throughout the study, until 28 days after the last dosing.)
- PK analysis of SGN1 level in blood.(For the first four infusions in Part 1 and Part 3)
- Bacterial shedding of SGN1 level in urine.(Before the first administration up to 28 days after the last dosing.)
- Bacterial shedding of SGN1 level in blood.(Before the first administration up to 28 days after the last dosing.)
- Bacterial shedding of SGN1 level in saliva.(Before the first administration up to 28 days after the last dosing.)
- Assessment of tumor colonization.(From receiving study drug and throughout the study, until 28 days after the last dosing.)
- Proinflammatory cytokines(Within 7 days prior to the first dose, and at 2, 4, 6, and 24 hours post end of first infusion.)