Study of SGN1 in Patients With Advanced Solid Tumor
- Registration Number
- NCT05038150
- Lead Sponsor
- Guangzhou Sinogen Pharmaceutical Co., Ltd
- 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).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 70
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Cohort SGN1 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 .
- Primary Outcome Measures
Name Time Method Objective response rate (ORR) 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. 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). 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) 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) 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 Outcome Measures
Name Time Method Bacterial shedding of SGN1 level in feces. Before the first administration up to 28 days after the last dosing. Feces samples for bacterial shedding will be collected by the patient before first administration of SGN1; this sample may be collected at any time during the screening period. Additional feces samples are to be collected after the end of the first infusion within the time frames below.
0-24 hours 24-48 hours 48-72 hours For subsequent SGN1 infusions (starting with Dose 2), will be collected by the subject within 72 hours prior to infusion and within 72 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).If samples collected around the first three doses result at or below the limit of detection (LOD), subsequent sample collection and testing is not required.
In EOT/ET visit, feces samples will be collected by the subject within 24 hours prior to the EOT/ET visit.Anti-Drug antibody (ADA) of SGN1. Before the first administration up to 28 days after the last dosing. Collecting of anti-drug antibodies (ADA) blood samples from all patients.
Blood samples will be collected before the each administration (within 2 days) for first 2 cycles and first administration of 3rd cycle (C1D1\~C3D1) and 24 hours (± 6 hours) post infusion for cycle 1 and cycle 2 (C1D2\~C2D23), and at the end of treatment/withdrawal visit.
The Subsequent ADA blood samples collection timepoints will be adjusted according to the subject's ADA analysis result.Incidence with any dose limiting toxicity (DLT),to determine the MTD. Up to 28 days post first dose. Any of the following judged to be associated with SGN1 (i.e., possibly-, probably-, or definitely related to), may be considered a DLT:
1. Any Grade 5 adverse event that is at least possibly related to investigational drug.
2. Non-hematological toxicities:
1. Grade 4 non-hematological toxicities (excluding alopecia) lasting \> 3 days despite optimal supportive care (OSC).
2. Grade 3 non-hematologic toxicities lasting \> 7 days despite optimal supportive care (OSC).
3. Hematological toxicities:
1. Grade 4 hematologic toxicity lasting \> 7 days (except following b and c).
2. Grade 3 or 4 febrile neutropenia (body temperature ≥38.5°C) lasting \> 7 days.
3. Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia.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. OBD will be determined by adverse events, preliminary efficacy data,and the OBD determined by the SMC.
PK analysis of SGN1 level in blood. For the first four infusions in Part 1 and Part 3 Concentrations of SGN1 will be measured. In Part 1 and Part 3, blood sampling for pharmacokinetics analyses will be conducted. The blood collection times for PK are within 30 minutes Pre-dose and immediately end of injection of first 4 infusions (C1D1, C1D8, C1D15 and C1D22);for first and fourth infusion(C1D1 and C1D22) extra blood sample needs to be collected at the following timepoints after the end of infusion procedure: 15 minutes (± 3 minute), 30 minutes (± 3 minute), 45 minutes (± 3 minute), 1 hour (± 5 minutes), 1.5 hours (± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 10 minutes) and every 30 minutes (± 3 minute) during the infusion procedure, besides, after the start time of infusion, following PK timepoints:24 hours ± 1 hour, 48 hours ± 1 hour and 72 hours ± 1 hour for C1D1 and C1D22.PK blood sampling points may be modified based on patients' PK parameters in future.
Bacterial shedding of SGN1 level in urine. Before the first administration up to 28 days after the last dosing. In Part 1 and Part 3, for the first SGN1 administration (C1D1), urine sampling for bacterial shedding will be conducted within 2 hours before administration, 3 hours ±1 hour, 6 hours ±1 hour, 24 hours ±3 hours, 48 hours ±3 hours and 72 hours ±3 hours after end of infusion.
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 ±3 hours post 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). If samples collected around the first three doses result at or below the limit of detection (LOD), subsequent sample collection and testing is not required.
In EOT/ET visit, urine samples for bacterial shedding will be collected.Bacterial shedding of SGN1 level in blood. Before the first administration up to 28 days after the last dosing. In Part 1 and Part 3 ,SGN1 blood concentrations before and after the first SGN1 infusion are measured in the PK Analysis described above. The qPCR results from PK blood samples will contribute to the analysis as the bacterial shedding of SGN1 in blood.
For subsequent SGN1 infusions (starting with Dose 2),blood samples shall be collected within 2 hours prior to the start of SGN1 infusion and 24 hours±3 hours post 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). If samples collected around the first three doses result at or below the limit of detection (LOD), subsequent sample collection and testing is not required.
In EOT/ET visit, blood samples for bacterial shedding will be collected.Bacterial shedding of SGN1 level in saliva. Before the first administration up to 28 days after the last dosing. For the first SGN1 administration (C1D1), saliva sampling for bacterial shedding will be conducted within 2 hours before administration, 3 hours ±1 hour, 6 hours ±1 hour, 24 hours ±3 hours, 48 hours ±3 hours and 72 hours ±3 hours after end of infusion.
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 ±3 hours post 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). If samples collected around the first three doses result at or below the limit of detection (LOD), subsequent sample collection and testing is not required.
In EOT/ET visit, saliva samples for bacterial shedding will be collected.Assessment of tumor colonization. From receiving study drug and throughout the study, until 28 days after the last dosing. For appropriate superficial tumors, colonization of the tumor by SGN1 will be assessed by fine needle aspiration and/or excise biopsies every 8 weeks.
Proinflammatory cytokines Within 7 days prior to the first dose, and at 2, 4, 6, and 24 hours post end of first infusion. Proinflammatory cytokines including IL-1β, IFN-γ,TNF-α, IL-6, and IL-8.
Trial Locations
- Locations (8)
Guangdong Clifford Hospital
🇨🇳Guangzhou, Guangdong, China
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
Health Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
Barbara Ann Karmanos Cancer Hospital dba Karmanos Cancer Center
🇺🇸Detroit, Michigan, United States
University of Cincinnati Cancer Center
🇺🇸Cincinnati, Ohio, United States
Harbin Medical University Cancer Hospital
🇨🇳Harbin, Heilongjiang, China
Shanghai Jiao Tong University Affiliated Sixth People's Hospital
🇨🇳Shanghai, Shanghai, China
West China Hospital of Sichuan University
🇨🇳Chengdu, Sichuan, China